194 results on '"Antonio Ferrer-Montiel"'
Search Results
2. β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity
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Cristina Martín-Escura, M. Ángeles Bonache, Jessy A. Medina, Alicia Medina-Peris, Jorge De Andrés-López, Sara González-Rodríguez, Sara Kerselaers, Gregorio Fernández-Ballester, Thomas Voets, Antonio Ferrer-Montiel, Asia Fernández-Carvajal, and Rosario González-Muñiz
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TRPM8 channel ,β-lactams ,antagonists ,docking ,antinociceptive activity ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca2+)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring C-terminal amides and diversely substituted N′-terminal monobenzyl groups in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca2+ entry, thereby establishing critical structure–activity relationships. While the substitution of the tert-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the N′-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the transient receptor potential (TRP) ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein. While the four main populated poses are located by the pore zone, a similar location to that described for the N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist cannot be discarded. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin (OXA).
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- 2023
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3. TRPV1 in chronic pruritus and pain: Soft modulation as a therapeutic strategy
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Asia Fernández-Carvajal, Gregorio Fernández-Ballester, and Antonio Ferrer-Montiel
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chronic pain ,pruritus ,therapeutic targets ,TRP channels ,soft drugs ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Chronic pain and pruritus are highly disabling pathologies that still lack appropriate therapeutic intervention. At cellular level the transduction and transmission of pain and pruritogenic signals are closely intertwined, negatively modulating each other. The molecular and cellular pathways involved are multifactorial and complex, including peripheral and central components. Peripherally, pain and itch are produced by subpopulations of specialized nociceptors that recognize and transduce algesic and pruritogenic signals. Although still under intense investigation, cumulative evidence is pointing to the thermosensory channel TRPV1 as a hub for a large number of pro-algesic and itchy agents. TRPV1 appears metabolically coupled to most neural receptors that recognize algesic and pruritic molecules. Thus, targeting TRPV1 function appears as a valuable and reasonable therapeutic strategy. In support of this tenet, capsaicin, a desensitizing TRPV1 agonist, has been shown to exhibit clinically relevant analgesic, anti-inflammatory, and anti-pruritic activities. However, potent TRPV1 antagonists have been questioned due to an hyperthermic secondary effect that prevented their clinical development. Thus, softer strategies directed to modulate peripheral TRPV1 function appear warranted to alleviate chronic pain and itch. In this regard, soft, deactivatable TRPV1 antagonists for topical or local application appear as an innovative approach for improving the distressing painful and itchy symptoms of patients suffering chronic pain or pruritus. Here, we review the data on these compounds and propose that this strategy could be used to target other peripheral therapeutic targets.
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- 2022
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4. Membrane Channels in Health and Diseases
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Antonio Felipe and Antonio Ferrer-Montiel
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n/a ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The goal of this Special Issue, entitled “Membrane Channels in Health and Diseases (https://www [...]
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- 2023
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5. A capsaicinoid-based soft drug, AG1529, for attenuating TRPV1-mediated histaminergic and inflammatory sensory neuron excitability
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Magdalena Nikolaeva-Koleva, Laura Butron, Sara González-Rodríguez, Isabel Devesa, Pierluigi Valente, Marta Serafini, Armando A. Genazzani, Tracey Pirali, Gregorio Fernández Ballester, Asia Fernández-Carvajal, and Antonio Ferrer-Montiel
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Medicine ,Science - Abstract
Abstract TRPV1, a member of the transient receptor potential (TRP) family, is a nonselective calcium permeable ion channel gated by physical and chemical stimuli. In the skin, TRPV1 plays an important role in neurogenic inflammation, pain and pruritus associated to many dermatological diseases. Consequently, TRPV1 modulators could represent pharmacological tools to respond to important patient needs that still represent an unmet medical demand. Previously, we reported the design of capsaicinoid-based molecules that undergo dermal deactivation (soft drugs), thus preventing their long-term dermal accumulation. Here, we investigated the pharmacological properties of the lead antagonist, 2-((4-hydroxy-2-iodo-5-methoxybenzyl) amino)-2-oxoethyl dodecanoate (AG1529), on heterologously expressed human TRPV1 (hTRPV1), on nociceptor excitability and on an in vivo model of acute pruritus. We report that AG1529 competitively blocked capsaicin-evoked activation of hTRPV1 with micromolar potency, moderately affected pH-induced gating, and did not alter voltage- and heat-mediated responses. AG1529 displays modest receptor selectivity as it mildly blocked recombinant hTRPA1 and hTRPM8 channels. In primary cultures of rat dorsal root ganglion (DRG) neurons, AG1529 potently reduced capsaicin-evoked neuronal firing. AG1529 exhibited lower potency on pH-evoked TRPV1 firing, and TRPA1-elicited nociceptor excitability. Furthermore, AG1529 abolished histaminergic and inflammation mediated TRPV1 sensitization in primary cultures of DRG neurons. Noteworthy, dermal wiping of AG1529, either in an acetone-based formulation or in an anhydrous ointment, dose-dependently attenuated acute histaminergic itch in a rodent model. This cutaneous anti-pruritic effect was devoid of the normal nocifensive action evoked by the burning sensation of capsaicin. Taken together, these preclinical results unveil the mode of action of AG1529 on TRPV1 channels and substantiate the tenet that this capsaicinoid-based soft drug is a promising candidate for drug development as a topical anti-pruritic and anti-inflammatory medication.
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- 2021
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6. Progress in the Structural Basis of thermoTRP Channel Polymodal Gating
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Gregorio Fernández-Ballester, Asia Fernández-Carvajal, and Antonio Ferrer-Montiel
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TRP channels ,thermoreceptors ,polymodality ,channel opening ,TRPV1 ,TRPM8 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The thermosensory transient receptor potential (thermoTRP) family of ion channels is constituted by several nonselective cation channels that are activated by physical and chemical stimuli functioning as paradigmatic polymodal receptors. Gating of these ion channels is achieved through changes in temperature, osmolarity, voltage, pH, pressure, and by natural or synthetic chemical compounds that directly bind to these proteins to regulate their activity. Given that thermoTRP channels integrate diverse physical and chemical stimuli, a thorough understanding of the molecular mechanisms underlying polymodal gating has been pursued, including the interplay between stimuli and differences between family members. Despite its complexity, recent advances in cryo-electron microscopy techniques are facilitating this endeavor by providing high-resolution structures of these channels in different conformational states induced by ligand binding or temperature that, along with structure-function and molecular dynamics, are starting to shed light on the underlying allosteric gating mechanisms. Because dysfunctional thermoTRP channels play a pivotal role in human diseases such as chronic pain, unveiling the intricacies of allosteric channel gating should facilitate the development of novel drug-based resolving therapies for these disorders.
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- 2023
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7. Comprehensive Survey of Consensus Docking for High-Throughput Virtual Screening
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Clara Blanes-Mira, Pilar Fernández-Aguado, Jorge de Andrés-López, Asia Fernández-Carvajal, Antonio Ferrer-Montiel, and Gregorio Fernández-Ballester
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molecular docking ,virtual screening ,consensus docking ,binding site ,scoring function ,drug discovery ,Organic chemistry ,QD241-441 - Abstract
The rapid advances of 3D techniques for the structural determination of proteins and the development of numerous computational methods and strategies have led to identifying highly active compounds in computer drug design. Molecular docking is a method widely used in high-throughput virtual screening campaigns to filter potential ligands targeted to proteins. A great variety of docking programs are currently available, which differ in the algorithms and approaches used to predict the binding mode and the affinity of the ligand. All programs heavily rely on scoring functions to accurately predict ligand binding affinity, and despite differences in performance, none of these docking programs is preferable to the others. To overcome this problem, consensus scoring methods improve the outcome of virtual screening by averaging the rank or score of individual molecules obtained from different docking programs. The successful application of consensus docking in high-throughput virtual screening highlights the need to optimize the predictive power of molecular docking methods.
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- 2022
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8. β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models
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Cristina Martín-Escura, Alicia Medina-Peris, Luke A. Spear, Roberto de la Torre Martínez, Luis A. Olivos-Oré, María Victoria Barahona, Sara González-Rodríguez, Gregorio Fernández-Ballester, Asia Fernández-Carvajal, Antonio R. Artalejo, Antonio Ferrer-Montiel, and Rosario González-Muñiz
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TRPM8 channels ,antagonist ,β–lactam ,oxaliplatin-induced peripheral neuropathy ,CCI chronic neuropathic ,nociception ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol-evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related diseases.
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- 2022
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9. Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain
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David Cabañero, Angela Ramírez-López, Eva Drews, Anne Schmöle, David M Otte, Agnieszka Wawrzczak-Bargiela, Hector Huerga Encabo, Sami Kummer, Antonio Ferrer-Montiel, Ryszard Przewlocki, Andreas Zimmer, and Rafael Maldonado
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neuropathic pain ,cannabinoid cb2 receptor ,operant drug self-administration ,spontaneous pain ,neuroimmune interactions ,neuronal and lymphocyte cannabinoid receptors ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Cannabinoid CB2 receptor (CB2) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB2; however, the involvement of CB2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2 agonist JWH133 in wild-type and knockout mice lacking CB2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2 disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB2 knockouts and was increased in mice defective in neuronal CB2 knockouts suggestive of increased spontaneous pain. Interestingly, CB2-positive lymphocytes infiltrated the injured nerve and possible CB2transfer from immune cells to neurons was found. Lymphocyte CB2depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB2that protects against spontaneous and evoked neuropathic pain.
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- 2020
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10. Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity
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María Ángeles Bonache, Pedro Juan Llabrés, Cristina Martín-Escura, Roberto De la Torre-Martínez, Alicia Medina-Peris, Laura Butrón, Isabel Gómez-Monterrey, Ana María Roa, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel, Asia Fernández-Carvajal, and Rosario González-Muñiz
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TRPM8 ,antagonists ,β–lactams ,absolute configuration ,Ca2+ microfluorimetry ,Patch-Clamp ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ non-selective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivatives, and began to intuit a possible effect of the stereogenic centers on the antagonist activity. To investigate the influence of configuration on the TRPM8 antagonist properties, here we prepare and characterize four possible diastereoisomeric derivatives of 4-benzyl-1-[(3′-phenyl-2′-dibenzylamino)prop-1′-yl]-4-benzyloxycarbonyl-3-methyl-2-oxoazetidine. In microfluorography assays, all isomers were able to reduce the menthol-induced cell Ca2+ entry to larger or lesser extent. Potency follows the order 3R,4R,2′R > 3S,4S,2′R ≅ 3R,4R,2′S > 3S,4S,2′S, with the most potent diastereoisomer showing a half inhibitory concentration (IC50) in the low nanomolar range, confirmed by Patch-Clamp electrophysiology experiments. All four compounds display high receptor selectivity against other members of the TRP family. Furthermore, in primary cultures of rat dorsal root ganglion (DRG) neurons, the most potent diastereoisomers do not produce any alteration in neuronal excitability, indicating their high specificity for TRPM8 channels. Docking studies positioned these β-lactams at different subsites by the pore zone, suggesting a different mechanism than the known N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist.
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- 2021
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11. Specific promoter deacetylation of histone H3 is conserved across mouse models of Huntington's disease in the absence of bulk changes
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Deisy Guiretti, Ana Sempere, Jose P. Lopez-Atalaya, Antonio Ferrer-Montiel, Angel Barco, and Luis M. Valor
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Huntington's disease ,Polyglutamine ,Epigenetics ,Histone acetylation ,Histone methylation ,Transcriptional dysregulation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Defective epigenetic regulation has been postulated as a possible cause for the extensive and premature transcriptional dysregulation observed in experimental models of Huntington's disease (HD). In this study, we extended our observations in the N171-82Q mouse strain relating to the limited impact of polyQ pathology on the global histone acetylation to other animal and cellular models of HD, namely the R6/1 and YAC128 strains, striatal-electroporated mice, primary neuronal cultures and stably transfected PC12 cells. In the absence of bulk chromatin changes, we nonetheless documented histone deacetylation events at the transcription start sites (TSS) of genes relevant to neuronal functions (e.g., Rin1, Plk5, Igfbp5, Eomes, and Fos). In some instances, these local deficits were associated with an increased susceptibility to transcriptional dysregulation (e.g., Camk1g and Rasl11b) and the defective trimethylation of histone H3 at lysine 4 (H3K4me3), another covalent modification of histone tails that is related to active transcription and is also altered in HD. Overall, this study provides further insight into the nature and extent of epigenetic dysregulation in HD pathology.
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- 2016
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12. Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification
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Marianna Dionisi, Federico Alessandro Ruffinatti, Beatrice Riva, Dmitry Lim, Annalisa Canta, Cristina Meregalli, Giulia Fumagalli, Laura Monza, Antonio Ferrer-Montiel, Asia Fernandez-Carvajal, Guido Cavaletti, Armando A. Genazzani, and Carla Distasi
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oxaliplatin ,TREK channels ,neuropathic pain ,pH ,DRG neurons ,Na+/H+ exchanger ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic acidification in dorsal root ganglion (DRG) neurons. Here, we investigated the early impact of oxaliplatin on the proton-sensitive TREK potassium channels. Following a 6-h oxaliplatin treatment, both channels underwent a transcription upregulation that returned to control levels after 42 h. The overexpression of TREK channels was also observed after in vivo treatment in DRG cells from mice exposed to acute treatment with oxaliplatin. Moreover, both intracellular pH and TREK channel transcription were similarly regulated after incubation with amiloride, an inhibitor of the Na+/H+ exchanger. In addition, we studied the role of oxaliplatin-induced acidification on channel behavior, and, as expected, we observed a robust positive modulation of TREK channel activity. Finally, we focused on the impact of this complex modulation on capsaicin-evoked neuronal activity finding a transient decrease in the average firing rate following 6 h of oxaliplatin treatment. In conclusion, the early activation of TREK genes may represent a mechanism of protection against the oxaliplatin-related perturbation of neuronal excitability.
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- 2020
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13. TRP Channels as Potential Targets for Sex-Related Differences in Migraine Pain
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Maite Artero-Morales, Sara González-Rodríguez, and Antonio Ferrer-Montiel
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TRP channels ,TRPV1 ,sex hormones ,estrogens ,migraine ,Biology (General) ,QH301-705.5 - Abstract
Chronic pain is one of the most debilitating human diseases and represents a social and economic burden for our society. Great efforts are being made to understand the molecular and cellular mechanisms underlying the pathophysiology of pain transduction. It is particularly noteworthy that some types of chronic pain, such as migraine, display a remarkable sex dimorphism, being up to three times more prevalent in women than in men. This gender prevalence in migraine appears to be related to sex differences arising from both gonadal and genetic factors. Indeed, the functionality of the somatosensory, immune, and endothelial systems seems modulated by sex hormones, as well as by X-linked genes differentially expressed during development. Here, we review the current data on the modulation of the somatosensory system functionality by gonadal hormones. Although this is still an area that requires intense investigation, there is evidence suggesting a direct regulation of nociceptor activity by sex hormones at the transcriptional, translational, and functional levels. Data are being accumulated on the effect of sex hormones on TRP channels such as TRPV1 that make pivotal contributions to nociceptor excitability and sensitization in migraine and other chronic pain syndromes. These data suggest that modulation of TRP channels' expression and/or activity by gonadal hormones provide novel pathways for drug intervention that may be useful for targeting the sex dimorphism observed in migraine.
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- 2018
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14. Sphingosine-1-Phosphate and the S1P3 Receptor Initiate Neuronal Retraction via RhoA/ROCK Associated with CRMP2 Phosphorylation
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Serena Quarta, Maria Camprubí-Robles, Rüdiger Schweigreiter, Dusan Matusica, Rainer V. Haberberger, Richard L. Proia, Christine E. Bandtlow, Antonio Ferrer-Montiel, and Michaela Kress
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S1P ,S1P3 ,neurite outgrowth ,axonal regeneration ,CRMP2 ,sensory neurons ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The bioactive lipid sphingosine-1-phosphate (S1P) is an important regulator in the nervous system. Here, we explored the role of S1P and its receptors in vitro and in preclinical models of peripheral nerve regeneration. Adult sensory neurons and motor neuron-like cells were exposed to S1P in an in vitro assay, and virtually all neurons responded with a rapid retraction of neurites and growth cone collapse which were associated with RhoA and ROCK activation. The S1P1 receptor agonist SEW2871 neither activated RhoA or neurite retraction, nor was S1P-induced neurite retraction mitigated in S1P1-deficient neurons. Depletion of S1P3 receptors however resulted in a dramatic inhibition of S1P-induced neurite retraction and was on the contrary associated with a significant elongation of neuronal processes in response to S1P. Opposing responses to S1P could be observed in the same neuron population, where S1P could activate S1P1 receptors to stimulate elongation or S1P3 receptors and retraction. S1P was, for the first time in sensory neurons, linked to the phosphorylation of collapsin response-mediated protein-2 (CRMP2), which was inhibited by ROCK inhibition. The improved sensory recovery after crush injury further supported the relevance of a critical role for S1P and receptors in fine-tuning axonal outgrowth in peripheral neurons.
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- 2017
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15. Trafficking of ThermoTRP Channels
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Clotilde Ferrandiz-Huertas, Sakthikumar Mathivanan, Christoph Jakob Wolf, Isabel Devesa, and Antonio Ferrer-Montiel
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TRP ,thermoTRP ,exocytosis ,SNARE ,protein-protein ,Chemical technology ,TP1-1185 ,Chemical engineering ,TP155-156 - Abstract
ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) channels that are activated by changes in the environmental temperature, from noxious cold to injurious heat. Acting as integrators of several stimuli and signalling pathways, dysfunction of these channels contributes to several pathological states. The surface expression of thermoTRPs is controlled by both, the constitutive and regulated vesicular trafficking. Modulation of receptor surface density during pathological processes is nowadays considered as an interesting therapeutic approach for management of diseases, such as chronic pain, in which an increased trafficking is associated with the pathological state. This review will focus on the recent advances trafficking of the thermoTRP channels, TRPV1, TRPV2, TRPV4, TRPM3, TRPM8 and TRPA1, into/from the plasma membrane. Particularly, regulated membrane insertion of thermoTRPs channels contributes to a fine tuning of final channel activity, and indeed, it has resulted in the development of novel therapeutic approaches with successful clinical results such as disruption of SNARE-dependent exocytosis by botulinum toxin or botulinomimetic peptides.
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- 2014
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16. Overexpression of P2X3 and P2X7 Receptors and TRPV1 Channels in Adrenomedullary Chromaffin Cells in a Rat Model of Neuropathic Pain
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Marina Arribas-Blázquez, Luis Alcides Olivos-Oré, María Victoria Barahona, Mercedes Sánchez de la Muela, Virginia Solar, Esperanza Jiménez, Javier Gualix, J. Michael McIntosh, Antonio Ferrer-Montiel, María Teresa Miras-Portugal, and Antonio R. Artalejo
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P2X3 receptors ,P2X7 receptors ,TRPV1 channels ,α9 nicotinic acetylcholine receptors ,neuropathic pain ,chromaffin cells ,adrenal medulla ,stress ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
We have tested the hypothesis that neuropathic pain acting as a stressor drives functional plasticity in the sympathoadrenal system. The relation between neuropathic pain and adrenal medulla function was studied with behavioral, immunohistochemical and electrophysiological techniques in rats subjected to chronic constriction injury of the sciatic nerve. In slices of the adrenal gland from neuropathic animals, we have evidenced increased cholinergic innervation and spontaneous synaptic activity at the splanchnic nerve–chromaffin cell junction. Likewise, adrenomedullary chromaffin cells displayed enlarged acetylcholine-evoked currents with greater sensitivity to α-conotoxin RgIA, a selective blocker of α9 subunit-containing nicotinic acetylcholine receptors, as well as increased exocytosis triggered by voltage-activated Ca2+ entry. Altogether, these adaptations are expected to facilitate catecholamine output into the bloodstream. Last, but most intriguing, functional and immunohistochemical data indicate that P2X3 and P2X7 purinergic receptors and transient receptor potential vanilloid-1 (TRPV1) channels are overexpressed in chromaffin cells from neuropathic animals. These latter observations are reminiscent of molecular changes characteristic of peripheral sensitization of nociceptors following the lesion of a peripheral nerve, and suggest that similar phenomena can occur in other tissues, potentially contributing to behavioral manifestations of neuropathic pain.
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- 2019
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17. The Spanish Ion Channel Initiative (SICI) Consortium: Ten Years (2008–2018) of a Network of Excellence on Ion Channel Research
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Antonio Felipe and Antonio Ferrer-Montiel
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n/a ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The Spanish Ion Channel Initiative consortium (SICI, http://sici. [...]
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- 2018
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18. New Strategies to Develop Novel Pain Therapies: Addressing Thermoreceptors from Different Points of View
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Antonio Ferrer-Montiel, José Manuel González-Ros, Isabel Devesa, Asia Fernández-Carvajal, and Gregorio Fernández-Ballester
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TRP channels ,nociceptor ,pain ,analgesia ,allosteric modulators ,receptor exocytosis ,protein-protein interactions ,novel targets ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
One approach to develop successful pain therapies is the modulation of dysfunctional ion channels that contribute to the detection of thermal, mechanical and chemical painful stimuli. These ion channels, known as thermoTRPs, promote the sensitization and activation of primary sensory neurons known as nociceptors. Pharmacological blockade and genetic deletion of thermoTRP have validated these channels as therapeutic targets for pain intervention. Several thermoTRP modulators have progressed towards clinical development, although most failed because of the appearance of unpredicted side effects. Thus, there is yet a need to develop novel channel modulators with improved therapeutic index. Here, we review the current state-of-the art and illustrate new pharmacological paradigms based on TRPV1 that include: (i) the identification of activity-dependent modulators of this thermoTRP channel; (ii) the design of allosteric modulators that interfere with protein-protein interaction involved in the functional coupling of stimulus sensing and gate opening; and (iii) the development of compounds that abrogate the inflammation-mediated increase of receptor expression in the neuronal surface. These new sites of action represent novel strategies to modulate pathologically active TRPV1, while minimizing an effect on the TRPV1 subpopulation involved in physiological and protective roles, thus increasing their potential therapeutic use.
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- 2011
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19. Ionic Channels as Targets for Drug Design: A Review on Computational Methods
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José Manuel González-Ros, Antonio Ferrer-Montiel, Gregorio Fernández-Ballester, and Asia Fernández-Carvajal
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virtual screening ,ion channel ,channelopathies ,quantitative structure–activity relationships ,homology models ,docking ,pharmacology ,in silico ,in vitro ,drug discovery ,computational approaches ,Pharmacy and materia medica ,RS1-441 - Abstract
Ion channels are involved in a broad range of physiological and pathological processes. The implications of ion channels in a variety of diseases, including diabetes, epilepsy, hypertension, cancer and even chronic pain, have signaled them as pivotal drug targets. Thus far, drugs targeting ion channels were developed without detailed knowledge of the molecular interactions between the lead compounds and the target channels. In recent years, however, the emergence of high-resolution structures for a plethora of ion channels paves the way for computer-assisted drug design. Currently, available functional and structural data provide an attractive platform to generate models that combine substrate-based and protein-based approaches. In silico approaches include homology modeling, quantitative structure-activity relationships, virtual ligand screening, similarity and pharmacophore searching, data mining, and data analysis tools. These strategies have been frequently used in the discovery and optimization of novel molecules with enhanced affinity and specificity for the selected therapeutic targets. In this review we summarize recent applications of in silico methods that are being used for the development of ion channel drugs.
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- 2011
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20. Solid-Phase Synthesis of New Trp(Nps)-Containing Dipeptide Derivatives as TRPV1 Channel Blockers
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Rosario González-Muñiz, Antonio Ferrer-Montiel, Asia Fernández-Carvajal, Fernando Albericio, Laura Zaccaro, Miriam Royo, Mª Teresa García-López, and Mª Jesús Pérez de Vega
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solid-phase ,Trp(Nps) dipeptides ,TRPV1 channel blockers ,Organic chemistry ,QD241-441 - Abstract
Trp(Nps)-Lys-NH2 derivatives, bearing alkyl or guanidine groups either at the N–terminus or on the Lys side-chain or at both positions were conveniently prepared on solid-phase and evaluated as TRPV1 channel antagonists.
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- 2010
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21. Adamantyl analogues of paracetamol as potent analgesic drugs via inhibition of TRPA1.
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Nieves Fresno, Ruth Pérez-Fernández, Carlos Goicoechea, Ibon Alkorta, Asia Fernández-Carvajal, Roberto de la Torre-Martínez, Susana Quirce, Antonio Ferrer-Montiel, M Isabel Martín, Pilar Goya, and José Elguero
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Medicine ,Science - Abstract
Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compound 6a/b, an analog of paracetamol, is not exerted through direct interaction with cannabinoid receptors, nor by inhibiting COX. It behaves as an interesting selective TRPA1 channel antagonist, which may be responsible for its analgesic properties, whereas it has no effect on the TRPM8 nor TRPV1 channels. The possibility of replacing a phenyl ring by an adamantyl ring opens new avenues in other fields of medicinal chemistry.
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- 2014
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22. Highly functionalized 1,2-diamino compounds through reductive amination of amino acid-derived β-keto esters.
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Paula Pérez-Faginas, M Teresa Aranda, M Teresa García-López, Lourdes Infantes, Asia Fernández-Carvajal, José Manuel González-Ros, Antonio Ferrer-Montiel, and Rosario González-Muñiz
- Subjects
Medicine ,Science - Abstract
1,2-Diamine derivatives are valuable building blocks to heterocyclic compounds and important precursors of biologically relevant compounds. In this respect, amino acid-derived β-keto esters are a suitable starting point for the synthesis of β,γ-diamino ester derivatives through a two-step reductive amination procedure with either simple amines or α-amino esters. AcOH and NaBH(3)CN are the additive and reducing agents of choice. The stereoselectivity of the reaction is still an issue, due to the slow imine-enamine equilibria through which the reaction occurs, affording mixtures of diastereoisomers that can be chromatographically separated. Transformation of the β,γ-diamino esters into pyrrolidinone derivatives allows the configuration assignment of the linear compounds, and constitutes an example of their potential application in the generation of molecular diversity.
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- 2013
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23. Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: awaiting peer review]
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Antonio Ferrer-Montiel
- Subjects
Review ,Articles ,Benzydamine hydrochloride ,sore throat ,oropharyngeal disorders ,inflammation ,pain relief ,nociceptor excitability - Abstract
Pain and inflammation are the consequences of sore throat, dental and oral procedures, infections, ulcers and head and neck chemotherapy/radiotherapy, and their management is of fundamental importance to avoid distress in patients. Benzydamine hydrochloride (HCl) is a topical indolic nonsteroidal anti-inflammatory drug, endowed with analgesic and anesthetic activity, and with antimicrobial (including both gram-positive and gram-negative bacteria) and antifungal properties (targeting Candida albicans and non-albicans strains), used in odontostomatology, otorhinolaryngology, and gynecology for its properties. This molecule has a lipophilic nature, showing high affinity with cell membranes and exhibiting membrane stabilization properties, resulting in local anesthesia, an effect related also to the interaction of the drug with cationic channels. In addition, benzydamine HCl is able to inhibit the production of pro-inflammatory cytokines, with consequent analgesia. Moreover, benzydamine HCl is able to inhibit leukocyte-endothelial interactions and platelet aggregation. Unlike other non-steroidal anti-inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase. Here we review the most updated clinical data available on benzydamine HCl local application as spray, mouthwash or gargling and evidence of its effectiveness in inflammatory and/or septic conditions in the otorhinolaryngology and odontostomatology settings, with particular reference to sore throat, oral inflammation, dental plaque, tonsillitis/tonsillectomy and chemo- or radiotherapy-induced oral mucositis. Novel formulations for oral administration of benzydamine HCl are also reviewed, including in situ gelling formulations to be sprayed onto the damaged oral mucosa. Finally, novel data on the potential role of benzydamine HCl in nociceptor excitability are introduced.
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- 2024
- Full Text
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24. First-in-Class Dual Hybrid Carbonic Anhydrase Inhibitors and Transient Receptor Potential Vanilloid 1 Agonists Revert Oxaliplatin-Induced Neuropathy
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Andrea Angeli, Laura Micheli, Fabrizio Carta, Marta Ferraroni, Tracey Pirali, Asia Fernandez Carvajal, Antonio Ferrer Montiel, Lorenzo Di Cesare Mannelli, Carla Ghelardini, and Claudiu T. Supuran
- Subjects
Drug Discovery ,Molecular Medicine - Published
- 2023
25. Design and validation of neuronal exocytosis blocking peptides as potential novel antiperspirants
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Laura Butron, Magdalena Nikolaeva‐Koleva, Ana Sempere, Verónica Rivero, Gregorio Fernandez‐Ballester, Ana Espinosa, Matteo Vergassola, Elena Mastrocola, Sara Zucchi, Lorella Ragni, Asia Fernández‐Carvajal, Giorgina Mangano, Antonio Ferrer‐Montiel, and Isabel Devesa
- Subjects
Dermatology ,Molecular Biology ,Biochemistry - Published
- 2023
26. Paclitaxel in vitro reversibly sensitizes the excitability of IB4(−) and IB4(+) sensory neurons from male and female rats
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Asia Fernandez-Carvajal, Roberto De la Torre-Martinez, Eva María Villalba Riquelme, and Antonio Ferrer-Montiel
- Subjects
Male ,Rats, Sprague-Dawley ,Pharmacology ,Paclitaxel ,Sensory Receptor Cells ,Ganglia, Spinal ,Animals ,Humans ,Peripheral Nervous System Diseases ,Antineoplastic Agents ,Female ,Rats, Wistar ,Rats - Abstract
Paclitaxel produces a chemotherapy-induced peripheral neuropathy that persists in 50-60% of cancer patients upon treatment. Evidence from animal models suggests an axonopathy of peripheral A- and C-type fibres that affects their excitability. However, direct effects of paclitaxel on sensory neuron excitability and sexual dimorphism remain poorly understood.We used a long-lasting (10 days in vitro) primary culture of rat dorsal root ganglion (DRG) neurons to investigate the time course effect of paclitaxel on the electrical activity of IB4(-) and IB4(+) sensory neurons of female and male adult Wistar rats.Paclitaxel strongly and reversibly stimulated spontaneous activity and augmented action potential tonic firing in IB4(-) and IB4(+) neurons in both sexes, peaking at 48 h post-treatment and virtually disappearing at 96 h. Paclitaxel decreased the current rheobase for action potential firing by reducing and accelerating the after-hyperpolarization phase. Molecularly, paclitaxel modulated NaOur data indicate that paclitaxel similarly potentiated IB4(-) and IB4(+) electrogenicity and uncover a potential sex dimorphism in paclitaxel-induced chemotherapy-induced peripheral neuropathy. Our in vitro, pre-clinical, chemotherapy-induced peripheral neuropathy paradigm provides a tool for studying the dynamics and underlying molecular mechanisms contributing to nociceptor sensitization in peripheral neuropathies and for testing desensitizing compounds.
- Published
- 2022
27. Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation
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David Alarcón-Alarcón, Xiang-Qun Xie, Asia Fernández-Carvajal, A.R.M. Ruhul Amin, Wade D. Van Horn, Yuanqiang Wang, Zhiwei Feng, Camila Montano, Tianjian Liang, Antonio Ferrer-Montiel, Denise C. Dawley, and V. Blair Journigan
- Subjects
Agonist ,010405 organic chemistry ,medicine.drug_class ,Stereochemistry ,Organic Chemistry ,Antagonist ,Icilin ,Ligand (biochemistry) ,01 natural sciences ,Biochemistry ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,TRPM8 ,medicine ,Menthol ,IC50 - Abstract
[Image: see text] TRPM8 antagonists derived from its cognate ligand, (−)-menthol, are underrepresented. We determine the absolute stereochemistry of a well-known TRPM8 antagonist, (−)-menthyl 1, using VCD and 2D NMR. We explore 1 for its antagonist effects of the human TRPM8 (hTRPM8) orthologue to uncover species-dependent inhibition versus rat channels. (−)-Menthyl 1 inhibits menthol- and icilin-evoked Ca(2+) responses at hTRPM8 with IC(50) values of 805 ± 200 nM and 1.8 ± 0.6 μM, respectively, while more potently inhibiting agonist responses at the rat orthologue (rTRPM8 IC(50) (menthol) = 117 ± 18 nM, IC(50) (icilin) = 521 ± 20 nM). Whole-cell patch-clamp recordings of hTRPM8 confirm the 1 inhibition of menthol-stimulated currents, with an IC(50) of 700 ± 200 nM. We demonstrate that 1 possesses ≥400-fold selectivity for hTRPM8 versus hTRPA1/hTRPV1. (−)-menthyl 1 can be used as a novel chemical tool to study hTRPM8 pharmacology and differences in species commonly used in drug discovery.
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- 2021
28. Targeting thermoTRP ion channels: in silico preclinical approaches and opportunities
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Gregorio Fernández-Ballester, Antonio Ferrer-Montiel, and Asia Fernández-Carvajal
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0301 basic medicine ,Pharmacology ,Virtual screening ,Chemistry ,In silico ,Clinical Biochemistry ,Computational biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Docking (molecular) ,030220 oncology & carcinogenesis ,Drug Discovery ,Molecular Medicine ,Ion channel ,ADME - Abstract
A myriad of cellular pathophysiological responses are mediated by polymodal ion channels that respond to chemical and physical stimuli such as thermoTRP channels. Intriguingly, these channels are p...
- Published
- 2020
29. Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity
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Rosario González-Muñiz, Carmen Cuevas, M. Angeles Bonache, Roberto de la Torre Martínez, Sara González-Rodríguez, Ana María Roa, Alicia Medina, Antonio Ferrer-Montiel, Asia Fernández-Carvajal, Gregorio Fernández-Ballester, Cristina Martín-Escura, and Andrés Francesch
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0301 basic medicine ,Male ,Models, Molecular ,Patch-Clamp Techniques ,Drug Evaluation, Preclinical ,lcsh:Medicine ,Medicinal chemistry ,Pharmacology ,Piperazines ,Transient receptor potential channel ,Mice ,0302 clinical medicine ,lcsh:Science ,Analgesics ,Multidisciplinary ,Molecular Structure ,Chemistry ,Peripheral Nervous System Diseases ,Chemical biology ,Cold Temperature ,Molecular Docking Simulation ,Oxaliplatin ,Allodynia ,Hyperalgesia ,Ion channels ,Cytophotometry ,medicine.symptom ,TRPM Cation Channels ,Antineoplastic Agents ,beta-Lactams ,Article ,03 medical and health sciences ,Structure-Activity Relationship ,Cell Line, Tumor ,TRPM8 ,medicine ,Animals ,Drug discovery and development ,Computer Simulation ,Binding site ,IC50 ,lcsh:R ,Antagonist ,030104 developmental biology ,Tumor progression ,Cell culture ,lcsh:Q ,030217 neurology & neurosurgery ,Transient receptor potential channels - Abstract
The cool sensor transient receptor potential melastatin channel 8 (TRPM8) is highly expressed in trigeminal and dorsal root ganglia, playing a key role in cold hypersensitivity associated to different peripheral neuropathies. Moreover, these channels are aberrantly expressed in different cancers, and seem to participate in tumor progression, survival and invasion. Accordingly, the search for potent and selective TRPM8 modulators attracted great interest in recent years. We describe new heterocyclic TRPM8 antagonist chemotypes derived from N-cloroalkyl phenylalaninol-Phe conjugates. The cyclization of these conjugates afforded highly substituted β-lactams and/or 2-ketopiperazine (KP) derivatives, with regioselectivity depending on the N-chloroalkyl group and the configuration. These derivatives behave as TRPM8 antagonists in the Ca2+ microfluorometry assay, and confirmed electrophysiologically for the best enantiopure β-lactams 24a and 29a (IC50, 1.4 and 0.8 µM). Two putative binding sites by the pore zone, different from those found for typical agonists and antagonists, were identified by in silico studies for both β-lactams and KPs. β-Lactams 24a and 29a display antitumor activity in different human tumor cell lines (micromolar potencies, A549, HT29, PSN1), but correlation with TRPM8 expression could not be established. Additionally, compound 24a significantly reduced cold allodynia in a mice model of oxaliplatin-induced peripheral neuropathy.
- Published
- 2020
30. ThermoTRP Channels in Pain Sexual Dimorphism: New Insights for Drug Intervention
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David, Cabañero, Eva, Villalba-Riquelme, Gregorio, Fernández-Ballester, Asia, Fernández-Carvajal, and Antonio, Ferrer-Montiel
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Male ,Pharmacology ,Analgesics ,Sex Characteristics ,History ,Polymers and Plastics ,Migraine Disorders ,Peripheral Nervous System Diseases ,Antineoplastic Agents ,Thermoreceptors ,Industrial and Manufacturing Engineering ,Transient Receptor Potential Channels ,Humans ,Female ,Pharmacology (medical) ,Chronic Pain ,Business and International Management - Abstract
Chronic pain is a major burden for the society and remains more prevalent and severe in females. The presence of chronic pain is linked to persistent alterations in the peripheral and the central nervous system. One of the main types of peripheral pain transducers are the transient receptor potential channels (TRP), also known as thermoTRP channels, which intervene in the perception of hot and cold external stimuli. These channels, and especially TRPV1, TRPA1 and TRPM8, have been subjected to profound investigation because of their role as thermosensors and also because of their implication in acute and chronic pain. Surprisingly, their sensitivity to endogenous signaling has been far less studied. Cumulative evidence suggests that the function of these channels may be differently modulated in males and females, in part through sexual hormones, and this could constitute a significant contributor to the sex differences in chronic pain. Here, we review the exciting advances in thermoTRP pharmacology for males and females in two paradigmatic types of chronic pain with a strong peripheral component: chronic migraine and chemotherapy-induced peripheral neuropathy (CIPN). The possibilities of peripheral druggability offered by these channels and the differential exploitation for men and women represent a development opportunity that will lead to a significant increment of the armamentarium of analgesic medicines for personalized chronic pain treatment.
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- 2022
31. Androgenic TRPM8 activity drives sexual dimorphism in a murine model of chronic migraine
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David Cabañero, Jorge de Andrés-López, Antonio Ferrer-Montiel, David Alarcón-Alarcón, Asia Fernández-Carvajal, and Gregorio Fernández-Ballester
- Subjects
Sexual dimorphism ,medicine.medical_specialty ,Endocrinology ,Chronic Migraine ,Murine model ,business.industry ,Internal medicine ,TRPM8 ,medicine ,business - Abstract
The mechanisms contributing to the high prevalence of chronic migraine in females are yet elusive. Here, we used a mouse model of nitroglycerin-induced chronic migraine that displays a sexual dimorphic phenotype and unveiled a role of TRPM8 as a testosterone receptor that provides antinociceptive resilience exclusively in males. Nitroglycerin induced similar mechanosensitivity to both sexes trough activation of TRPA1 channels, but triggered persistent hypersensitivity solely in females, as males readily recovered from the migraine crisis. Notably, we found that testosterone exerted an antinociceptive activity through its interaction with the TRPM8 channel. Downregulation of this protective mechanism in males led to persistent mechanical hypersensitivity, whereas administration of testosterone to females favoured their recovery. Thus, our findings reveal a novel protective function of TRPM8 through pre-clinical models of acute and chronic pain and highlights the interest of molecular solutions mimicking the pain-relieving activity of testosterone on TRPM8.
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- 2021
32. TRPM8 contributes to sex dimorphism by promoting recovery of normal sensitivity in a mouse model of chronic migraine
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David Alarcón-Alarcón, David Cabañero, Jorge de Andrés-López, Magdalena Nikolaeva-Koleva, Simona Giorgi, Gregorio Fernández-Ballester, Asia Fernández-Carvajal, and Antonio Ferrer-Montiel
- Subjects
Male ,Sex Characteristics ,Multidisciplinary ,Migraine Disorders ,General Physics and Astronomy ,TRPM Cation Channels ,Membrane Proteins ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Transient Receptor Potential Channels ,Receptors, Androgen ,Animals ,Humans ,Female ,Calcium ,Testosterone ,TRPA1 Cation Channel - Abstract
TRPA1 and TRPM8 are transient receptor potential channels expressed in trigeminal neurons that are related to pathophysiology in migraine models. Here we use a mouse model of nitroglycerine-induced chronic migraine that displays a sexually dimorphic phenotype, characterized by mechanical hypersensitivity that develops in males and females, and is persistent up to day 20 in female mice, but disappears by day 18 in male mice. TRPA1 is required for development of hypersensitivity in males and females, whereas TRPM8 contributes to the faster recovery from hypersensitivity in males. TRPM8-mediated antinociception effects required the presence of endogenous testosterone in males. Administration of exogenous testosterone to females and orchidectomized males led to recovery from hypersensitivity. Calcium imaging and electrophysiological recordings in in vitro systems confirmed testosterone activity on murine and human TRPM8, independent of androgen receptor expression. Our findings suggest a protective function of TRPM8 in shortening the time frame of hypersensitivity in a mouse model of migraine.
- Published
- 2021
33. Recent progress in non-opioid analgesic peptides
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Antonio Ferrer-Montiel, Rosario González-Muñiz, M. Jesús Pérez de Vega, Ministerio de Economía, Industria y Competitividad (España), and Consejo Superior de Investigaciones Científicas (España)
- Subjects
0301 basic medicine ,Protein-protein interactions ,medicine.medical_treatment ,Analgesic ,Biophysics ,Pain ,Calcitonin gene-related peptide ,Pharmacology ,Biochemistry ,Ion Channels ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,chemistry.chemical_compound ,Transient receptor potential channel ,GPCR ,0302 clinical medicine ,Animals ,Humans ,Medicine ,Molecular Targeted Therapy ,Receptor ,Molecular Biology ,Ion channel ,G protein-coupled receptor ,business.industry ,Analgesics, Non-Narcotic ,030104 developmental biology ,chemistry ,Analgesic peptides ,Ion channels ,Cannabinoid ,business ,030217 neurology & neurosurgery ,Neurotensin - Abstract
Pain is a prevalent complex medical problem, characterized by physically debilitating and mentally destabilizing conditions. Current pain therapeutics mainly include non-steroidal anti-inflammatory drugs and narcotics (opioids), but they exhibit limitations in efficacy, unwanted side effects and the problem of drug abuse. To overcome these issues, the discovery of different molecular players within pain pathways could lead to new opportunities for therapeutic intervention. Among other strategies, peptides could be powerful pharmaceutical agents for effective opioid-free medications for pain treatment. This review is a compendium of representative non-opioid analgesic peptides acting directly or indirectly at different ion channels and receptors distributed in nociceptive pathways. They include peptides targeting Ca, Na and K voltage-gated ion channels, the neuronal nicotinic receptors (nAChR), transient receptor potential channels (TRP), and different non-opioid G-protein coupled receptors (GPCRs), like the calcitonin gen-related peptide (CGRP), cannabinoid, bradykinin and neurotensin receptors, among others. Peptides engineered from protein-protein interactions among pain-related receptors and regulatory proteins also led to new therapeutic approaches for pain management. Following some successful examples, already in the clinics or under clinical trials, the improved understanding of pain mechanisms, and the advances in peptide permeation and/or delivery, could afford new analgesic peptides in the near future., This work was supported by the Spanish Ministry of Economy and Competitiveness [SAF 2015-66275-C2-R]; and Consejo Superior de Investigaciones Científicas, Spain (201580E073, 201880E109).
- Published
- 2018
34. DD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target
- Author
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Héctor Zamora-Carreras, Daniel Butrón, Ana Baamonde, Olga Abian, Isabel Devesa, Miguel A. Treviño, Sara González-Rodríguez, Adrián Velázquez-Campoy, Asia Fernández-Carvajal, Rosario González-Muñiz, Laura Lagartera, M. Angeles Bonache, M. Angeles Jiménez, Mercedes Martín-Martínez, Antonio Ferrer-Montiel, Ministerio de Economía y Competitividad (España), European Commission, and Consejo Superior de Investigaciones Científicas (España)
- Subjects
Male ,Calcitonin Gene-Related Peptide ,Pain ,Molecular modeling ,Peptide ,Ala-scan ,Molecular Dynamics Simulation ,DD04107 ,Biochemistry ,Synaptotagmin 1 ,Exocytosis ,Lipopeptides ,Mice ,Structure-Activity Relationship ,Drug Discovery ,Animals ,CGRP ,Molecular Biology ,Protein secondary structure ,chemistry.chemical_classification ,Analgesics ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Isothermal titration calorimetry ,Biological activity ,Cyclic peptide ,NMR ,Synaptotagmin I ,Biophysics ,Synaptotagmin-1 ,Analgesia ,SNARE complex - Abstract
15 pags, 8 figs, 3 tabs. -- Supplementary data to this article can be found online at https://doi.org/10.1016/j.bioorg.2021.105231., The analgesic peptide DD04107 (Pal-EEMQRR-NH2) and its acetylated analogue inhibit α-calcitonin gene-related peptide (α-CGRP) exocytotic release from primary sensory neurons. Examining the crystal structure of the SNARE-Synaptotagmin-1(Syt1) complex, we hypothesized that these peptides could inhibit neuronal exocytosis by binding to Syt1, hampering at least partially its interaction with the SNARE complex. To address this hypothesis, we first interrogate the role of individual side-chains on the inhibition of α-CGRP release, finding that E1, M3, Q4 and R6 residues were crucial for activity. CD and NMR conformational analysis showed that linear peptides have tendency to adopt α-helical conformations, but the results with cyclic analogues indicated that this secondary structure is not needed for activity. Isothermal titration calorimetry (ITC) measurements demonstrate a direct interaction of some of these peptides with Syt1-C2B domain, but not with Syt7-C2B region, indicating selectivity. As expected for a compound able to inhibit α-CGRP release, cyclic peptide derivative Pal-E-cyclo[EMQK]R-NH2 showed potent in vivo analgesic activity, in a model of inflammatory pain. Molecular dynamics simulations provided a model consistent with KD values for the interaction of peptides with Syt1-C2B domain, and with their biological activity. Altogether, these results identify Syt1 as a potential new analgesic target., This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO-FEDER), RTI2018-097189-C2 and CTQ2017-84371-P), and the Spanish National Research Council (CSIC, 201880E109, 201980E030). The NMR experiments were performed in the “Manuel Rico” NMR laboratory, LMR, CSIC, a node of the Spanish Large-Scale National Facility ICTS R-LRB. We thank Prof. Josep Rizo and R. Voleti (Dept. Biophysics, Biochemistry and Pharmacology, UT Southwestern Medical Center, Dallas, USA) for providing the clones required for expressing Syt1 and Syt7 proteins. SG-R and AB belong to the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA).
- Published
- 2021
35. Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity
- Author
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Gregorio Fernández-Ballester, Pedro Juan Llabrés, Alicia Medina-Peris, Rosario González-Muñiz, Asia Fernández-Carvajal, Laura Butron, Maria Angeles Bonache, Roberto de la Torre-Martínez, Isabel Gomez-Monterrey, Cristina Martín-Escura, Ana María Roa, Antonio Ferrer-Montiel, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Comunidad de Madrid, Consejo Superior de Investigaciones Científicas (España), Bonache, María Ángeles [0000-0002-4922-5345], Llabrés, Pedro Juan, Martín-Escura, Cristina, González-Muñiz, Rosario [0000-0001-8833-4328], Bonache, M. A., Llabres, P. J., Martin-Escura, C., De la Torre-Martinez, R., Medina-Peris, A., Butron, L., Gomez-Monterrey, I., Roa, A. M., Fernandez-Ballester, G., Ferrer-Montiel, A., Fernandez-Carvajal, A., Gonzalez-Muniz, R., Bonache, María Ángeles, and González-Muñiz, Rosario
- Subjects
Ca ,Phenylalanine ,β–lactams ,lcsh:Chemistry ,chemistry.chemical_compound ,TRPM ,Ganglia, Spinal ,lcsh:QH301-705.5 ,Ca2+ microfluorimetry ,Spectroscopy ,Cells, Cultured ,Neurons ,antagonists ,Chemistry ,β–lactam ,General Medicine ,Computer Science Applications ,Molecular Docking Simulation ,Lactam ,TRPM Cation Channel ,TRPM8 ,Patch-Clamp ,Stereochemistry ,2+ ,TRPM Cation Channels ,microfluorimetry ,beta-Lactams ,Catalysis ,Article ,Inorganic Chemistry ,Structure-Activity Relationship ,Animals ,Absolute configuration ,Patch clamp ,Physical and Theoretical Chemistry ,Molecular Biology ,IC50 ,Ion channel ,Animal ,Patch- Clamp ,Organic Chemistry ,Antagonist ,Neuron ,Rats ,absolute configuration ,lcsh:Biology (General) ,lcsh:QD1-999 ,Rat ,Antagonists - Abstract
Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ non-selective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivatives, and began to intuit a possible effect of the stereogenic centers on the antagonist activity. To investigate the influence of configuration on the TRPM8 antagonist properties, here we prepare and characterize four possible diastereoisomeric derivatives of 4-benzyl-1-[(30-phenyl-20- dibenzylamino)prop-10-yl]-4-benzyloxycarbonyl-3-methyl-2-oxoazetidine. In microfluorography assays, all isomers were able to reduce the menthol-induced cell Ca2+ entry to larger or lesser extent. Potency follows the order 3R,4R,20R > 3S,4S,20R =3R,4R,20S > 3S,4S,20S, with the most potent diastereoisomer showing a half inhibitory concentration (IC50) in the low nanomolar range, confirmed by Patch-Clamp electrophysiology experiments. All four compounds display high receptor selectivity against other members of the TRP family. Furthermore, in primary cultures of rat dorsal root ganglion (DRG) neurons, the most potent diastereoisomers do not produce any alteration in neuronal excitability, indicating their high specificity for TRPM8 channels. Docking studies positioned these β-lactams at different subsites by the pore zone, suggesting a different mechanism than the known N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist., This research was funded by the Spanish Ministerio de Ciencia y Universidades (MICYUFEDER, RTI2018-097189-C2-1 to A.F.-M. and A.F.-C., and RTI2018-097189-C2-2 to R.G.M.), Comunidad de Madrid (IND2017/BMD7673 to R.G.-M.) and the Spanish National Research Council (CSIC, 201980E030 to R.G.-M.).
- Published
- 2020
36. Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification
- Author
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Federico Alessandro Ruffinatti, Asia Fernández-Carvajal, Armando A. Genazzani, Dmitry Lim, G Fumagalli, Laura Monza, Marianna Dionisi, Beatrice Riva, Guido Cavaletti, Cristina Meregalli, Annalisa Canta, Antonio Ferrer-Montiel, Carla Distasi, Dionisi, M, Ruffinatti, F, Riva, B, Lim, D, Canta, A, Meregalli, C, Fumagalli, G, Monza, L, Ferrer-Montiel, A, Fernandez-Carvajal, A, Cavaletti, G, Genazzani, A, and Distasi, C
- Subjects
Male ,Potassium Channels ,Patch-Clamp Techniques ,H ,Action Potentials ,Stimulation ,exchanger ,lcsh:Chemistry ,Amiloride ,Mice ,Dorsal root ganglion ,Models ,Ganglia, Spinal ,Na+/H+ exchanger ,Premovement neuronal activity ,DRG neurons ,DRG neuron ,lcsh:QH301-705.5 ,Inbred BALB C ,Tandem Pore Domain ,Spectroscopy ,Neurons ,Mice, Inbred BALB C ,Sodium-Hydrogen Exchanger 1 ,Chemistry ,pH ,Peripheral Nervous System Diseases ,General Medicine ,Hydrogen-Ion Concentration ,Electrophysiology ,Na ,+ ,Neuropathic pain ,Oxaliplatin ,PH ,TREK channels ,TRPV1 ,Animals ,Antineoplastic Agents ,Capsaicin ,Epithelial Sodium Channel Blockers ,Humans ,Models, Biological ,Potassium Channels, Tandem Pore Domain ,Primary Cell Culture ,Transcriptional Activation ,Potassium channel ,Computer Science Applications ,Cell biology ,medicine.anatomical_structure ,medicine.drug ,Spinal ,Intracellular pH ,Catalysis ,Article ,Inorganic Chemistry ,medicine ,Patch clamp ,Physical and Theoretical Chemistry ,Molecular Biology ,neuropathic pain ,Organic Chemistry ,oxaliplatin ,Biological ,electrophysiology ,digestive system diseases ,stomatognathic diseases ,lcsh:Biology (General) ,lcsh:QD1-999 ,TREK channel ,Ganglia - Abstract
Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic acidification in dorsal root ganglion (DRG) neurons. Here, we investigated the early impact of oxaliplatin on the proton-sensitive TREK potassium channels. Following a 6-h oxaliplatin treatment, both channels underwent a transcription upregulation that returned to control levels after 42 h. The overexpression of TREK channels was also observed after in vivo treatment in DRG cells from mice exposed to acute treatment with oxaliplatin. Moreover, both intracellular pH and TREK channel transcription were similarly regulated after incubation with amiloride, an inhibitor of the Na+/H+ exchanger. In addition, we studied the role of oxaliplatin-induced acidification on channel behavior, and, as expected, we observed a robust positive modulation of TREK channel activity. Finally, we focused on the impact of this complex modulation on capsaicin-evoked neuronal activity finding a transient decrease in the average firing rate following 6 h of oxaliplatin treatment. In conclusion, the early activation of TREK genes may represent a mechanism of protection against the oxaliplatin-related perturbation of neuronal excitability.
- Published
- 2020
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37. Structure-based design of novel biphenyl amide antagonists of human transient receptor potential cation channel subfamily M member 8 channels (TRPM8)
- Author
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Antonio Ferrer Montiel, Velvet Blair Journigan, and Asia Fernandez Carvajal
- Published
- 2020
38. Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain
- Author
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Antonio Ferrer-Montiel, David M. Otte, Anne Schmöle, Sami Kummer, Ryszard Przewlocki, David Cabañero, Andreas Zimmer, Agnieszka Wawrzczak-Bargiela, Hector Huerga Encabo, Rafael Maldonado, Angela Ramírez-López, and Eva Drews
- Subjects
Male ,0301 basic medicine ,Lymphocyte ,medicine.medical_treatment ,Self Administration ,Monocytes ,Mice ,Random Allocation ,neuroimmune interactions ,0302 clinical medicine ,Cannabinoid receptor type 2 ,Medicine ,Biology (General) ,Receptors, Cannabinoid ,Mice, Knockout ,Neurons ,General Neuroscience ,Human biology ,General Medicine ,operant drug self-administration ,medicine.anatomical_structure ,Nociception ,Neuropathic pain ,Knockout mouse ,lipids (amino acids, peptides, and proteins) ,Research Article ,QH301-705.5 ,Science ,Protective Agents ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Immune system ,Animals ,Human Biology and Medicine ,mouse ,Gene knockout ,Cannabinoid Receptor Agonists ,neuropathic pain ,cannabinoid cb2 receptor ,General Immunology and Microbiology ,Cannabinoids ,business.industry ,spontaneous pain ,neuronal and lymphocyte cannabinoid receptors ,Mice, Inbred C57BL ,030104 developmental biology ,Neuralgia ,Cannabinoid ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Cannabinoid CB2 receptor (CB2) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB2; however, the involvement of CB2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2 agonist JWH133 in wild-type and knockout mice lacking CB2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2 disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB2 knockouts and was increased in mice defective in neuronal CB2 knockouts suggestive of increased spontaneous pain. Interestingly, CB2-positive lymphocytes infiltrated the injured nerve and possible CB2transfer from immune cells to neurons was found. Lymphocyte CB2depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB2that protects against spontaneous and evoked neuropathic pain. This paper was supported by the following grants: European Commission NeuroPain, FP7-602891-2 to Rafael Maldonado. Instituto de Salud Carlos III RTA, RD16/0017/0020/FEDER to Rafael Maldonado. Ministerio de Ciencia, Innovación y Universidades SAF2017-84060-R FEDER to Rafael Maldonado. Generalitat de Catalunya SGR2017-669, ICREA Academia Award 2015 to Rafael Maldonado. Generalitat de Catalunya 2018 FI_B 00207 to Angela Ramírez-López. Polish Ministry of Science and Education 3070/7.PR/2014/2 to Ryszard Przewlocki. Spanish Ministry of Science, Innovation and Universities 2018-097189-B-C21 to Antonio Ferrer-Montiel. Universidad Miguel Hernandez UMH-PAR2019 to Antonio Ferrer-Montiel.
- Published
- 2020
39. Author response: Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain
- Author
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David M. Otte, Anne Schmöle, Sami Kummer, Ryszard Przewlocki, Eva Drews, Antonio Ferrer-Montiel, David Cabañero, Angela Ramírez-López, Rafael Maldonado, Hector Huerga Encabo, Agnieszka Wawrzczak-Bargiela, and Andreas Zimmer
- Subjects
business.industry ,medicine.medical_treatment ,Neuropathic pain ,medicine ,Cannabinoid receptor type 2 ,Cannabinoid ,business ,Neuroscience - Published
- 2020
40. A capsaicinoid-based soft drug, AG1529, for attenuating TRPV1-mediated histaminergic and inflammatory sensory neuron excitability
- Author
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Pierluigi Valente, Laura Butron, Gregorio Fernández Ballester, Antonio Ferrer-Montiel, Tracey Pirali, Sara González-Rodríguez, Marta Serafini, Asia Fernández-Carvajal, Armando A. Genazzani, Isabel Devesa, and Magdalena Nikolaeva-Koleva
- Subjects
Sensory Receptor Cells ,Science ,TRPV1 ,TRPV Cation Channels ,Pharmacology ,Ion channels in the nervous system ,Article ,Transient receptor potential channel ,chemistry.chemical_compound ,Dorsal root ganglion ,Receptor pharmacology ,Ganglia, Spinal ,Drug Discovery ,medicine ,Humans ,Inflammation ,Neurogenic inflammation ,Multidisciplinary ,Chemistry ,Histaminergic ,Sensory neuron ,medicine.anatomical_structure ,nervous system ,Capsaicin ,Nociceptor ,Medicine ,Laurates ,Histamine - Abstract
TRPV1, a member of the transient receptor potential (TRP) family, is a nonselective calcium permeable ion channel gated by physical and chemical stimuli. In the skin, TRPV1 plays an important role in neurogenic inflammation, pain and pruritus associated to many dermatological diseases. Consequently, TRPV1 modulators could represent pharmacological tools to respond to important patient needs that still represent an unmet medical demand. Previously, we reported the design of capsaicinoid-based molecules that undergo dermal deactivation (soft drugs), thus preventing their long-term dermal accumulation. Here, we investigated the pharmacological properties of the lead antagonist, 2-((4-hydroxy-2-iodo-5-methoxybenzyl) amino)-2-oxoethyl dodecanoate (AG1529), on heterologously expressed human TRPV1 (hTRPV1), on nociceptor excitability and on an in vivo model of acute pruritus. We report that AG1529 competitively blocked capsaicin-evoked activation of hTRPV1 with micromolar potency, moderately affected pH-induced gating, and did not alter voltage- and heat-mediated responses. AG1529 displays modest receptor selectivity as it mildly blocked recombinant hTRPA1 and hTRPM8 channels. In primary cultures of rat dorsal root ganglion (DRG) neurons, AG1529 potently reduced capsaicin-evoked neuronal firing. AG1529 exhibited lower potency on pH-evoked TRPV1 firing, and TRPA1-elicited nociceptor excitability. Furthermore, AG1529 abolished histaminergic and inflammation mediated TRPV1 sensitization in primary cultures of DRG neurons. Noteworthy, dermal wiping of AG1529, either in an acetone-based formulation or in an anhydrous ointment, dose-dependently attenuated acute histaminergic itch in a rodent model. This cutaneous anti-pruritic effect was devoid of the normal nocifensive action evoked by the burning sensation of capsaicin. Taken together, these preclinical results unveil the mode of action of AG1529 on TRPV1 channels and substantiate the tenet that this capsaicinoid-based soft drug is a promising candidate for drug development as a topical anti-pruritic and anti-inflammatory medication.
- Published
- 2020
41. A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA(1)), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration
- Author
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Giovanni Cincilla, Cristina Rosell del Valle, Rubèn López-Vales, Silvia Ortega-Gutiérrez, Maria Puigdomenech, Fernando Rodríguez de Fonseca, Melchor Sanchez-Martinez, Jerold Chun, Gloria Hernández-Torres, Antonio Ferrer-Montiel, Debora Zian, María L. López-Rodríguez, Isabel Devesa, Sakthikumar Mathivanan, Richard Rivera, Henar Vázquez-Villa, R Fernando Martínez, Inés González-Gil, Yasuyuki Kihara, Nora Khiar-Fernández, and Emma Zambrana-Infantes
- Subjects
Models, Molecular ,Agonist ,Sensory Receptor Cells ,medicine.drug_class ,media_common.quotation_subject ,Population ,Pharmacology ,Hydrocarbons, Aromatic ,01 natural sciences ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Cell Movement ,Drug Discovery ,Lysophosphatidic acid ,medicine ,Animals ,Humans ,Rats, Wistar ,Receptors, Lysophosphatidic Acid ,Internalization ,education ,Receptor ,Cells, Cultured ,030304 developmental biology ,media_common ,Analgesics ,0303 health sciences ,education.field_of_study ,Chronic pain ,Pain Perception ,medicine.disease ,0104 chemical sciences ,Mice, Inbred C57BL ,010404 medicinal & biomolecular chemistry ,chemistry ,Neuropathic pain ,Neuralgia ,Molecular Medicine ,Female ,lipids (amino acids, peptides, and proteins) ,Autotaxin - Abstract
Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA(1)) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA(1) agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA(1) receptor agonist described so far (E(max) = 118%, EC(50) = 0.24 µM, K(D) = 19.6 nM; inactive at autotaxin and LPA(2-6) receptors). This compound induces characteristic LPA(1)-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.
- Published
- 2020
42. Structure-Based Design of Novel Biphenyl Amide Antagonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 8 Channels with Potential Implications in the Treatment of Sensory Neuropathies
- Author
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Colleen E. Heffner, Saifur Rahman, Yuanqiang Wang, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel, V. Blair Journigan, Nicholas Bachtel, Xiang-Qun Xie, Asia Fernández-Carvajal, Wade D. Van Horn, A.R.M. Ruhul Amin, Taufiq Rahman, Sara González-Rodríguez, Siyi Wang, Jacob K. Hilton, and Zhiwei Feng
- Subjects
Patch-Clamp Techniques ,Physiology ,Cognitive Neuroscience ,TRPM Cation Channels ,Biochemistry ,Article ,03 medical and health sciences ,Transient receptor potential channel ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,Transient Receptor Potential Channels ,Amide ,TRPM8 ,medicine ,Humans ,Homology modeling ,IC50 ,030304 developmental biology ,0303 health sciences ,Chemistry ,Biphenyl Compounds ,Antagonist ,Peripheral Nervous System Diseases ,Cell Biology ,General Medicine ,Small molecule ,Amides ,Menthol ,Allodynia ,HEK293 Cells ,Hyperalgesia ,Biophysics ,Calcium ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Structure–activity relationship studies of a reported menthol-based transient receptor potential cation channel subfamily M member 8 channel (TRPM8) antagonist, guided by computational simulations and structure-based design, uncovers a novel series of TRPM8 antagonists with >10-fold selectivity versus related TRP subtypes. Spiro[4.5]decan-8-yl analogue 14 inhibits icilin-evoked Ca(2+) entry in HEK-293 cells stably expressing human TRPM8 (hTRPM8) with an IC(50) of 2.4 ± 1.0 nM, while in whole-cell patch-clamp recordings this analogue inhibits menthol-evoked currents with a hTRPM8 IC(50) of 64 ± 2 nM. Molecular dynamics (MD) simulations of compound 14 in our homology model of hTRPM8 suggest that this antagonist forms extensive hydrophobic contacts within the orthosteric site. In the wet dog shakes (WDS) assay, compound 14 dose-dependently blocks icilin-triggered shaking behaviors in mice. Upon local administration, compound 14 dose dependently inhibits cold allodynia evoked by the chemotherapy oxaliplatin in a murine model of peripheral neuropathy at microgram doses. Our findings suggest that 14 and other biphenyl amide analogues within our series can find utility as potent antagonist chemical probes derived from (−)-menthol as well as small molecule therapeutic scaffolds for chemotherapy-induced peripheral neuropathy (CIPN) and other sensory neuropathies.
- Published
- 2019
43. Targeting Transient Receptor Potential Vanilloid 1 (TRPV1) Channel Softly: The Discovery of Passerini Adducts as a Topical Treatment for Inflammatory Skin Disorders
- Author
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Fabio Seiti, Franco Pattarino, Armando A. Genazzani, Asia Fernández-Carvajal, Isabel Devesa, Cristina Travelli, Silvio Aprile, Marta Serafini, Tracey Pirali, Laura Butron, Giorgio Grosa, Alessia Griglio, Giovanni Sorba, Antonio Ferrer-Montiel, and Sara González-Rodríguez
- Subjects
Keratinocytes ,0301 basic medicine ,Administration, Topical ,TRPV1 ,TRPV Cation Channels ,Inflammation ,Pharmacology ,Skin Diseases ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Transient receptor potential channel ,0302 clinical medicine ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Cells, Cultured ,Drug discovery ,Antagonist ,Analgesics, Non-Narcotic ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Capsaicin ,Hyperalgesia ,Molecular Medicine ,Female ,medicine.symptom ,Laurates ,030217 neurology & neurosurgery - Abstract
Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and the development of new capsaicinoids is a promising pharmacological approach in the management of skin disorders related to inflammation and pruritus. Here we report the synthesis and the evaluation of capsaicin soft drugs that undergo deactivation by the hydrolyzing activity of skin esterases. The implanting of an ester group in the lipophilic moiety of capsaicinoids by the Passerini multicomponent reaction affords both agonists and antagonists that retain transient receptor potential vanilloid 1 channel (TRPV1) modulating activity and, at the same time, are susceptible to hydrolysis. The most promising antagonist identified shows in vivo anti-nociceptive activity on pruritus and hyperalgesia without producing hyperthermia, thus validating it as novel treatment for dermatological conditions that implicate TRPV1 channel dysfunction.
- Published
- 2018
44. Amino acid and peptide prodrugs of diphenylpropanones positive allosteric modulators of α7 nicotinic receptors with analgesic activity
- Author
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Lieve Naesens, María Jesús Pérez de Vega, Rosario González-Muñiz, Adrián Plata, Francisco Sala, Sara González-Rodríguez, Antonio Ferrer-Montiel, José Mulet, Beatriz Balsera, Asia Fernández-Carvajal, Salvador Sala, Roberto de la Torre-Martínez, Manuel Criado, Ministerio de Economía, Industria y Competitividad (España), Generalitat Valenciana, and European Commission
- Subjects
Male ,0301 basic medicine ,alpha7 Nicotinic Acetylcholine Receptor ,Xenopus ,Freund's Adjuvant ,Allosteric regulation ,Pain ,Peptide ,Diketopiperazines ,Pharmacology ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Allosteric Regulation ,Valine ,Drug Discovery ,DDP-IV ,Animals ,Edema ,Humans ,Structure–activity relationship ,Prodrugs ,Amino Acids ,Rats, Wistar ,Allosteric modulation ,Ion channel ,Pain Measurement ,Inflammation ,chemistry.chemical_classification ,Analgesics ,Dose-Response Relationship, Drug ,Molecular Structure ,Phenylpropionates ,Diphenylpropanones ,Organic Chemistry ,Biological activity ,General Medicine ,Prodrug ,Rats ,Amino acid ,030104 developmental biology ,chemistry ,Biochemistry ,a7 nicotinic receptors ,Peptides ,030217 neurology & neurosurgery - Abstract
α7 Nicotinic acetylcholine receptors (nAChRs) are ion channels implicated in a number of CNS pathological processes, including pain and psychiatric, cognitive and inflammatory diseases. Comparing with orthosteric agonism, positive allosteric modulation of these channels constitutes an interesting approach to achieve selectivity versus other nicotinic receptors. We have recently described new chalcones and 1,3-diphenylpropanones as positive allosteric modulators (PAMs) of α7 nAChRs, which proved to have good analgesic activities but poor pharmacokinetic properties. Here we report the preparation of amino acid and peptide derivatives as prodrugs of these modulators with the aim of improving their in vivo biological activity. While the valine derivative showed very short half life in aqueous solutions to be considered a prodrug, Val-Val and Val-Pro-Val are suitable precursors of the parent 1,3-diphenylpropanones, via chemical and enzymatic transformation, respectively. Compounds 19 (Val-Val) and 21 (Val-Pro-Val), prodrugs of the 2′,5′,4-trihydroxy-1,3-diphenylpropan-1-one 3, showed significant antinociceptive activity in in vivo assays. The best compound, 21, displayed a better profile in the analgesia test than its parent compound 3, exhibiting about the same potency but long-lasting effects., Funding: This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO) SAF2011-22802, BFU2015- 70067-REDC and SAF2015-66275-C2-R, and the Generalitat Valenciana, PROMETEO/2014/011. BBP thanks the CSIC for a predoctoral fellowship (JAE-Predoc from Junta para la Ampliación de Estudios, co-financed by FSE).
- Published
- 2018
45. 1-(2′,5′-dihydroxyphenyl)-3-(2-fluoro-4-hydroxyphenyl)-1-propanone (RGM079): A positive allosteric modulator of α7 nicotinic receptors with analgesic and neuroprotective activity
- Author
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Marta Miguel, Salvador Sala, Manuel Criado, Asia Fernández-Carvajal, María Jesús Pérez de Vega, Antonio Ferrer-Montiel, José Mullet, Francisco Sala, Rosario González-Muñiz, Roberto de la Torre Martínez, Manuela G. López, Cristina Fernández-Mendívil, Silvia Moreno-Fernández, Sara González-Rodríguez, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), European Commission, and Comunidad de Madrid
- Subjects
Agonist ,Allosteric modulator ,alpha7 Nicotinic Acetylcholine Receptor ,Physiology ,medicine.drug_class ,Cell Survival ,Cognitive Neuroscience ,Allosteric regulation ,Pain ,Pharmacology ,Biochemistry ,Neuroprotection ,03 medical and health sciences ,0302 clinical medicine ,Allosteric Regulation ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Receptor ,Allosteric modulation ,030304 developmental biology ,Acetylcholine receptor ,Pain Measurement ,Inflammation ,Neurons ,0303 health sciences ,Analgesics ,Chemistry ,Diphenylpropanones ,Biological activity ,Cell Biology ,General Medicine ,Rats ,α7 Nicotinic receptors ,Neuroprotective Agents ,Analgesia ,Alzheimer disease ,030217 neurology & neurosurgery ,Acetylcholine ,medicine.drug - Abstract
Acetylcholine α7 nicotinic receptors are widely expressed in the brain, where they are involved in the central processing of pain as well as in neuropsychiatric, neurodegenerative, and inflammatory processes. Positive allosteric modulators (PAMs) show the advantage of allowing the selective regulation of different subtypes of acetylcholine receptors without directly interacting with the agonist binding site. Here, we report the preparation and biological activity of a fluoro-containing compound, 1-(2′,5′-dihydroxyphenyl)-3-(2-fluoro-4-hydroxyphenyl)-1-propanone (8, RGM079), that behaves as a potent PAM of the α7 receptors and has a balanced pharmacokinetic profile and antioxidant properties comparable or even higher than well-known natural polyphenols. In addition, compound RGM079 shows neuroprotective properties in Alzheimer's disease (AD)-toxicity related models. Thus, it causes a concentration-dependent neuroprotective effect against the toxicity induced by okadaic acid (OA) in the human neuroblastoma cell line SH-SY5Y. Similarly, in primary cultures of rat cortical neurons, RGM079 is able to restore the cellular viability after exposure to OA and amyloid peptide Aβ, with cell death almost completely prevented at 10 and 30 μM, respectively. Finally, compound RGM079 shows in vivo analgesic activity in the complete Freund's adjuvant (CFA)-induced paw inflammation model after intraperitoneal administration., This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (MINECO-FEDER) grant number SAF2015-66275-C2-R and RTI2018-097189-C2 to RGM and AFM, and RTI2018-095793-B-I00 to MGL, the Comunidad de Madrid/European Union Ref S2017/BMD-3827 to MGL and the CSIC, grant number 201980E030 to RGM.
- Published
- 2019
46. The calmodulin-binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3
- Author
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Albert Vallejo-Gracia, Daniel Sastre, Laura Solé, Antonio Serrano-Albarrás, Sara R. Roig, Antonio Ferrer-Montiel, Antonio Felipe, Gregorio Fernández-Ballester, and Michael M. Tamkun
- Subjects
0301 basic medicine ,Subfamily ,Calmodulin ,Protein subunit ,In silico ,Amino Acid Motifs ,Biochemistry ,complex mixtures ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Leukocytes ,Genetics ,Animals ,Humans ,Leukocyte proliferation ,natural sciences ,Molecular Biology ,Kv1.3 Potassium Channel ,biology ,Chemistry ,urogenital system ,Endoplasmic reticulum ,KCNE4 ,Potassium channel ,Rats ,Cell biology ,HEK293 Cells ,030104 developmental biology ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,nervous system ,Potassium Channels, Voltage-Gated ,biology.protein ,biological phenomena, cell phenomena, and immunity ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Item does not contain fulltext The voltage-dependent potassium (Kv) channel Kv1.3 regulates leukocyte proliferation, activation, and apoptosis, and altered expression of this channel is linked to autoimmune diseases. Thus, the fine-tuning of Kv1.3 function is crucial for the immune system response. The Kv1.3 accessory protein, potassium voltage-gated channel subfamily E (KCNE) subunit 4, acts as a dominant negative regulatory subunit to both enhance inactivation and induce intracellular retention of Kv1.3. Mutations in KCNE4 also cause immune system dysfunction. Although the formation of Kv1.3-KCNE4 complexes has profound consequences for leukocyte physiology, the molecular determinants involved in the Kv1.3-KCNE4 association are unknown. We now show that KCNE4 associates with Kv1.3 via a tetraleucine motif situated within the carboxy-terminal domain of this accessory protein. This motif would function as an interaction platform, in which Kv1.3 and Ca(2+)/calmodulin compete for the KCNE4 interaction. Finally, we propose a structural model of the Kv1.3-KCNE4 complex. Our experimental data and the in silico structure suggest that the KCNE4 interaction hides a forward-trafficking motif within Kv1.3 in addition to adding a strong endoplasmic reticulum retention signature to the Kv1.3-KCNE4 complex. Thus, the oligomeric composition of the Kv1.3 channelosome fine-tunes the precise balance between anterograde and intracellular retention elements that control the cell surface expression of Kv1.3 and immune system physiology.-Sole, L., Roig, S. R., Sastre, D., Vallejo-Gracia, A., Serrano-Albarras, A., Ferrer-Montiel, A., Fernandez-Ballester, G., Tamkun, M. M., Felipe, A. The calmodulin-binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3. 01 juli 2019
- Published
- 2019
47. Whirlin increases TRPV1 channel expression and cellular stability
- Author
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María Camprubí-Robles, Jun Yang, Natalia Cuesta, Antonio Ferrer-Montiel, Amparo Andrés-Borderia, Maria Grazia Ciardo, Pierluigi Valente, and Rosa Planells-Cases
- Subjects
Nociception ,0301 basic medicine ,Scaffold protein ,Proteasome Endopeptidase Complex ,PDZ domain ,TRPV Cation Channels ,Pain ,Biology ,Cytoskeleton ,PDZ ,Synapsis ,Thermosensory ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Gene silencing ,RNA, Small Interfering ,Rats, Wistar ,Molecular Biology ,Cells, Cultured ,Regulation of gene expression ,Protein Stability ,musculoskeletal, neural, and ocular physiology ,Membrane Proteins ,Nociceptors ,Cell Biology ,Rats ,Cell biology ,030104 developmental biology ,Gene Expression Regulation ,nervous system ,Membrane protein ,Proteasome ,Multiprotein Complexes ,Proteolysis ,lipids (amino acids, peptides, and proteins) ,Receptor clustering ,psychological phenomena and processes ,030217 neurology & neurosurgery - Abstract
The expression and function of TRPV1 are influenced by its interaction with cellular proteins. Here, we identify Whirlin, a cytoskeletal PDZ-scaffold protein implicated in hearing, vision and mechanosensory transduction, as an interacting partner of TRPV1. Whirlin associates with TRPV1 in cell lines and in primary cultures of rat nociceptors. Whirlin is expressed in 55% of mouse sensory C-fibers, including peptidergic and non-peptidergic nociceptors, and co-localizes with TRPV1 in 70% of them. Heterologous expression of Whirlin increased TRPV1 protein expression and trafficking to the plasma membrane, and promoted receptor clustering. Silencing Whirlin expression with siRNA or blocking protein translation resulted in a concomitant degradation of TRPV1 that could be prevented by inhibiting the proteasome. The degradation kinetics of TRPV1 upon arresting protein translation mirrored that of Whirlin in cells co-expressing both proteins, suggesting a parallel degradation mechanism. Noteworthy, Whirlin expression significantly reduced TRPV1 degradation induced by prolonged exposure to capsaicin. Thus, our findings indicate that Whirlin and TRPV1 are associated in a subset of nociceptors and that TRPV1 protein stability is increased through the interaction with the cytoskeletal scaffold protein. Our results suggest that the Whirlin-TRPV1 complex may represent a novel molecular target and its pharmacological disruption might be a therapeutic strategy for the treatment of peripheral TRPV1-mediated disorders. (C) 2015 Elsevier B.V. All rights reserved.
- Published
- 2016
48. TRP Channels as Potential Targets for Sex-Related Differences in Migraine Pain
- Author
-
Sara González-Rodríguez, Antonio Ferrer-Montiel, and Maite Artero-Morales
- Subjects
0301 basic medicine ,TRPV1 ,Review ,Bioinformatics ,sex hormones ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Biochemistry ,03 medical and health sciences ,Transient receptor potential channel ,0302 clinical medicine ,Medicine ,Molecular Biosciences ,migraine ,lcsh:QH301-705.5 ,Molecular Biology ,Sensitization ,TRP channels ,business.industry ,Chronic pain ,medicine.disease ,Sexual dimorphism ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,Migraine ,Nociceptor ,business ,030217 neurology & neurosurgery ,estrogens ,Hormone - Abstract
Chronic pain is one of the most debilitating human diseases and represents a social and economic burden for our society. Great efforts are being made to understand the molecular and cellular mechanisms underlying the pathophysiology of pain transduction. It is particularly noteworthy that some types of chronic pain, such as migraine, display a remarkable sex dimorphism, being up to three times more prevalent in women than in men. This gender prevalence in migraine appears to be related to sex differences arising from both gonadal and genetic factors. Indeed, the functionality of the somatosensory, immune, and endothelial systems seems modulated by sex hormones, as well as by X-linked genes differentially expressed during development. Here, we review the current data on the modulation of the somatosensory system functionality by gonadal hormones. Although this is still an area that requires intense investigation, there is evidence suggesting a direct regulation of nociceptor activity by sex hormones at the transcriptional, translational, and functional levels. Data are being accumulated on the effect of sex hormones on TRP channels such as TRPV1 that make pivotal contributions to nociceptor excitability and sensitization in migraine and other chronic pain syndromes. These data suggest that modulation of TRP channels' expression and/or activity by gonadal hormones provide novel pathways for drug intervention that may be useful for targeting the sex dimorphism observed in migraine.
- Published
- 2018
49. Effect of a novel TRPV1 antagonist on capsaicin nociceptors
- Author
-
Laura García, Antonio Ferrer Montiel, Armando, Asia Fernández Carvajal, Tracey, and Isabel Devesa Giner
- Subjects
Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Chemistry ,Capsaicin ,Antagonist ,TRPV1 ,Nociceptor ,Pharmacology - Published
- 2018
50. Identification of a Potent Tryptophan-Based TRPM8 Antagonist with in Vivo Analgesic Activity
- Author
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Sara González-Rodríguez, Marina Sala, Alessia Bertamino, Nunzio Iraci, Veronica Di Sarno, Ilaria Mosca, Paolo Ambrosino, Carmine Ostacolo, Pietro Campiglia, Giacomo Pepe, Ettore Novellino, Maurizio Taglialatela, Simona Musella, Tania Ciaglia, Asia Fernández-Carvajal, Antonio Ferrer-Montiel, Isabel Gomez-Monterrey, Maria Virginia Soldovieri, Bertamino, Alessia, Iraci, Nunzio, Ostacolo, Carmine, Ambrosino, Paolo, Musella, Simona, Di Sarno, Veronica, Ciaglia, Tania, Pepe, Giacomo, Sala, Marina, Soldovieri, Maria Virginia, Mosca, Ilaria, Gonzalez-Rodriguez, Sara, Fernández-Carvajal, Asia, Ferrer-Montiel, Antonio, Novellino, Ettore, Taglialatela, Maurizio, Campiglia, Pietro, and Gomez-Monterrey, Isabel M.
- Subjects
Models, Molecular ,0301 basic medicine ,Tryptamine ,Analgesic ,Pharmaceutical Science ,TRPM Cation Channels ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Models ,Drug Discovery ,Analgesics, Animals, HEK293 Cells, Humans, Hyperalgesia, Mice, Models, Molecular, Structure-Activity Relationship, TRPM Cation Channels, Tryptophan, Drug Design ,TRPM8 ,Animals ,Humans ,IC50 ,Analgesics ,Chemistry ,Drug Discovery3003 Pharmaceutical Science ,Tryptophan ,Antagonist ,Molecular ,In vitro ,030104 developmental biology ,HEK293 Cells ,Hyperalgesia ,Molecular Medicine ,Drug Design - Abstract
TRPM8 has been implicated in nociception and pain and is currently regarded as an attractive target for the pharmacological treatment of neuropathic pain syndromes. A series of analogues of N, N'-dibenzyl tryptamine 1, a potent TRPM8 antagonist, was prepared and screened using a fluorescence-based in vitro assay based on menthol-evoked calcium influx in TRPM8 stably transfected HEK293 cells. The tryptophan derivative 14 was identified as a potent (IC50 0.2 ± 0.2 nM) and selective TRPM8 antagonist. In vivo, 14 showed significant target coverage in both an icilin-induced WDS (at 1-30 mg/kg s.c.) and oxaliplatin-induced cold allodynia (at 0.1-1 μg s.c.) mice models. Molecular modeling studies identified the putative binding mode of these antagonists, suggesting that they could influence an interaction network between the S1-4 transmembrane segments and the TRP domains of the channel subunits. The tryptophan moiety provides a new pharmacophoric scaffold for the design of highly potent modulators of TRPM8-mediated pain.
- Published
- 2018
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