27 results on '"McMurray, Gordon"'
Search Results
2. A bladder-cooling reflex in the anaesthetised guinea-pig: A model of the positive clinical ice-water test
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Gardiner, Jennifer C., McMurray, Gordon, and Westbrook, Simon
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URINARY organs , *BLADDER , *PRESSURE , *URINATION - Abstract
Abstract: Introduction: In patients with detrusor hyperreflexia, intravesical instillation of ice-cold water results in the development of involuntary bladder contractions at volumes less than normal cystometric capacity. This is referred to as a positive ice-water test (+IWT) and can be reversed by vanilloid receptor agonists and potentiated by menthol. The present study was designed to investigate the existence of an analogous cooling reflex in the guinea-pig bladder that could be used as a small animal model in order to test the effects of drugs on the reflex. Methods: Bladder pressure and external urethral sphincter electromyogram (EUS EMG) were recorded in α-chloralose/urethane anaesthetised guinea-pigs during rapid infusion of cold or warm saline into the bladder with or without prior intravesical exposure to menthol or resiniferatoxin (RTX). Results: The mean control micturition threshold volume (TV) of 2.58 ml at 38 °C was reduced to 1.52 ml in response to saline infusion at 3 °C (P =0.001). The cold-induced reduction in TV was reproducible during several subsequent repeat infusions at 38 °C and 3 °C and was accompanied by decreases in bladder voiding pressure. The duration of the micturition reflex was markedly increased following cold compared with warm saline infusion (mean 24.5 s at 3 °C, 10.2 s at 38 °C, P =0.001) and was associated with oscillations in bladder pressure and concomitant bursting activity in the EUS EMG. During step-wise decreases in infusate temperature from 38 °C to 23 °C, 15 °C, 7 °C and 3 °C, the threshold infusate temperature to elicit a significant reduction in TV was 15 °C. The reduction in TV at 3 °C was potentiated by intravesical infusion of 0.6 mM menthol whilst intravesical infusion of 500 nM RTX reversed the reduction in TV at 3 °C. Discussion: These data suggest that a bladder-cooling reflex is present in the anaesthetised guinea-pig and represents a useful small animal model of the clinical +IWT. [Copyright &y& Elsevier]
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- 2007
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3. Pudendal nerve stimulation of a preparation of isolated guinea-pig urethra.
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Walters, Richard D., McMurray, Gordon, and Brading, Alison F.
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PUDENDAL nerve , *NERVOUS system , *NEURAL stimulation , *ELECTROPHYSIOLOGY , *GUINEA pigs as laboratory animals , *URETHRA , *UROLOGY - Abstract
OBJECTIVE To assess the functional response of the urethral striated muscle to activation of its nerves, using a novel isolated organ-bath preparation. MATERIALS AND METHODS The urethra of the female guinea-pig was chosen as a suitable model for investigation, as it is functionally and structurally similar to the human urethra. Female Dunkin–Hartley guinea-pigs (400–500 g) were used; for the histochemical and immunohistochemical experiments, unfixed urethras were cryo-sectioned (14 µm thick) and were stained using established methods. For in vitro experiments, whole urethras were suspended vertically, with pudendal nerves intact, for isometric tension and intraluminal pressure recording in a 40-mL organ bath. Drugs were applied directly to the bathing solution. RESULTS In the striated muscle layer of the urethra there was positive β-NADPH-diaphorase activity. In organ-bath studies the pudendal nerve-evoked contractions (0.2 ms pulses, 5 s trains, 70 V and 1–100 Hz) were abolished in the presence of tubocurarine (10−6m), and unaffected by guanethidine and atropine (both 10−6m). Pre-incubation with sodium nitroprusside and SIN-1 chloride significantly reduced the initial peak pressure responses ( P < 0.05,anova for paired data) evoked by electrical field stimulation of the pudendal nerves at stimulus parameters of 0.2 ms pulses, 5 s trains, 70 V and 25 Hz. CONCLUSION Electrically induced contractions were abolished by tubocurarine, confirming that the pudendal nerve innervates the striated muscle of the guinea-pig external urethral sphincter via nicotinic receptors. β-NADPH-diaphorase histochemistry gave positive staining around guinea-pig striated muscle cells and possibly identified neuromuscular junction sites staining positively for the nitric oxide synthase marker. Together with the results of the organ-bath experiments, the results suggest that the striated muscle cells of the guinea-pig urethra have the machinery to respond to nitric oxide. [ABSTRACT FROM AUTHOR]
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- 2006
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4. Animal models in urological disease and sexual dysfunction.
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McMurray, Gordon, Casey, James H., and Naylor, Alasdair M.
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URINARY organ diseases , *URINARY organs , *SEXUAL dysfunction , *URINARY incontinence , *BLADDER , *PROSTATE hypertrophy - Abstract
There are several conditions associated with dysfunction of the lower urinary tract or which result in a reduction in the ability to engage in satisfactory sexual function and result in significant bother to sufferers, partners and/or carers. This review describes some of the animal models that may be used to discover safe and effective medicines with which to treat them. While alpha adrenoceptor antagonists and 5-alpha-reductase inhibitors deliver improvement in symptom relief in benign prostatic hyperplasia sufferers, the availability of efficacious and well-tolerated medicines to treat incontinence is less well served. Stress urinary incontinence (SUI) has no approved medical therapy in the United States and overactive bladder (OAB) therapy is limited to treatment with muscarinic antagonists (anti-muscarinics). SUI and OAB are characterised by high prevalence, a growing ageing population and a strong desire from sufferers and physicians for more effective treatment options. High patient numbers with low presentation rates characterizes sexual dysfunction in men and women. The introduction of Viagra™ in 1998 for treating male erectile dysfunction and the success of the phosphodiesterase type 5 inhibitor class (PDE5 inhibitor) have indicated the willingness of sufferers to seek treatment when an effective alternative to injections and devices is available. The main value of preclinical models in discovering new medicines is to predict clinical outcomes. This translation can be established relatively easily in areas of medicine where there are a large number of drugs with different underlying pharmacological mechanisms in clinical usage. However, apart from, for example, the use of PDE5 inhibitors to treat male erectile dysfunction and the use of anti-muscarinics to treat OAB, this clinical information is limited. Therefore, current confidence in existing preclinical models is based on our understanding of the biochemical, physiological, pathophysiological and psychological mechanisms underlying the conditions in humans and how they are reflected in preclinical models. Confidence in both the models used and the pharmacological data generated is reinforced if different models of related aspects of the same disorder generate confirmatory data. However, these models will only be fully validated in retrospect once the pharmacological agents they have helped identify are tested in humans.British Journal of Pharmacology (2006) 147, S62–S79. doi:10.1038/sj.bjp.0706630 [ABSTRACT FROM AUTHOR]
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- 2006
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5. Functional Innervation of Guinea-Pig Bladder Interstitial Cells of Cajal Subtypes: Neurogenic Stimulation Evokes In Situ Calcium Transients.
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Gray, Susannah M., McGeown, J. Graham, McMurray, Gordon, and McCloskey, Karen D.
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INTERSTITIAL cells , *TETRODOTOXIN , *ATROPINE , *NERVES , *NEUROGENIC bladder , *BLADDER diseases - Abstract
Several populations of interstitial cells of Cajal (ICC) exist in the bladder, associated with intramural nerves. Although ICC respond to exogenous agonists, there is currently no evidence of their functional innervation. The objective was to determine whether bladder ICC are functionally innervated. Guinea-pig bladder tissues, loaded with fluo-4AM were imaged with fluorescent microscopy and challenged with neurogenic electrical field stimulation (EFS). All subtypes of ICC and smooth muscle cells (SMC) displayed spontaneous Ca2+-oscillations. EFS (0.5 Hz, 2 Hz, 10 Hz) evoked tetrodotoxin (1 µM)- sensitive Ca2+-transients in lamina propria ICC (ICC-LP), detrusor ICC and perivascular ICC (PICC) associated with mucosal microvessels. EFS responses in ICC-LP were significantly reduced by atropine or suramin. SMC and vascular SMC (VSM) also responded to EFS. Spontaneous Ca2+-oscillations in individual ICC-LP within networks occurred asynchronously whereas EFS evoked coordinated Ca2+-transients in all ICC-LP within a field of view. Non-correlated Ca2+-oscillations in detrusor ICC and adjacent SMC pre-EFS, contrasted with simultaneous neurogenic Ca2+ transients evoked by EFS. Spontaneous Ca2+- oscillations in PICC were little affected by EFS, whereas large Ca2+-transients were evoked in pre-EFS quiescent PICC. EFS also increased the frequency of VSM Ca2+-oscillations. In conclusion, ICC-LP, detrusor ICC and PICC are functionally innervated. Interestingly, Ca2+-activity within ICC-LP networks and between detrusor ICC and their adjacent SMC were synchronous under neural control. VSM and PICC Ca2+-activity was regulated by bladder nerves. These novel findings demonstrate functional neural control of bladder ICC. Similar studies should now be carried out on neurogenic bladder to elucidate the contribution of impaired nerve-ICC communication to bladder pathophysiology. [ABSTRACT FROM AUTHOR]
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- 2013
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6. 5-HT2A receptor activation of the external urethral sphincter and 5-HT2C receptor inhibition of micturition: A study based on pharmacokinetics in the anaesthetized female rat
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Mbaki, Yvonne, Gardiner, Jennifer, McMurray, Gordon, and Ramage, Andrew G.
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SEROTONIN receptors , *URETERS , *SPHINCTERS , *URINATION , *PHARMACOKINETICS , *DOSAGE forms of drugs , *DRUG infusion pumps , *LABORATORY rats - Abstract
Abstract: Central and peripheral 5-hydroxytryptamine (5-HT) receptors play a critical role in the regulation of micturition. Bolus doses of 5-HT2A/2C receptor agonists have been shown to activate the external urethral sphincter (EUS) and to inhibit micturition. This study was designed to determine the contribution of these two 5-HT receptor subtypes to activation of the EUS and inhibition of micturition utilising pharmacokinetic knowledge to better control drug exposure. Recordings of urethral and bladder pressure, EUS-Electromyogram (EMG), the micturition reflex induced by bladder filling, blood pressure and heart rate were made in anaesthetized female rats. The effects of intravenous (i.v.) infusions of the 5-HT2 receptor agonist (2S)-1-(6-chloro-5-fluoroindol-1-yl)propan-2-amine fumarate (Ro 60-0175) in the absence or presence of the selective 5-HT2C receptor antagonist 6-chloro-5-methyl-N-[6-(2-methylpyridin-3-yl)oxypyridin-3-yl]-2,3-dihydroindole-1-carboxamide dihydrochloride (SB 242084) or 5-HT2A receptor antagonist (R)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (MDL-100,907) were studied on these variables. Continuous infusion of increasing concentrations of Ro 60-0175 only evoked EUS-EMG activity at the highest concentration, which was blocked by co-infusion of MDL-100,907 but not SB 242084. Urethral pressure was unaffected by any drug infusion. Ro 60-0175 at the lowest concentration inhibited the micturition reflex but as the concentration increased this was reversed to facilitation. SB 242084 blocked the inhibition while MDL-100,907 blocked the excitation. Activation of 5-HT2A not 5-HT2C receptors evoked EUS-EMG activity. In conclusion, 5-HT2A receptor activation facilitated the micturition reflex and evoked EUS-EMG while 5-HT2C receptor activation only inhibited the micturition reflex. [Copyright &y& Elsevier]
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- 2012
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7. Novel 2-imidazoles as potent and selective α1A adrenoceptor partial agonists
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Whitlock, Gavin A., Conlon, Kelly, McMurray, Gordon, Roberts, Lee R., Stobie, Alan, and Thurlow, Richard J.
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ADRENERGIC receptors , *DRUG receptors , *IMIDAZOLES , *AZOLES - Abstract
Abstract: Novel 2-imidazoles have been identified as potent partial agonists of the α1A adrenergic receptor, with good selectivity over the α1B, α1D and α2A receptor sub-types. Sulfonamide 23 possessed attractive drug-like properties with respect to physicochemical and ADME properties and wide ligand selectivity. [Copyright &y& Elsevier]
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- 2008
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8. Barrington's nucleus in the guinea pig (Cavia porcellus): Location in relation to noradrenergic cell groups and connections to the lumbosacral spinal cord
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Kuipers, Rutger, Eggens-Meijer, Ellie, and McMurray, Gordon
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CELL nuclei , *URINATION , *CENTRAL nervous system , *NERVOUS system - Abstract
Abstract: Micturition is largely controlled by Barrington''s nucleus in the dorsolateral tegmentum of the pons. This nucleus coordinates simultaneous bladder contraction and external urethral sphincter relaxation, by means of a specific pattern of projections to the lumbosacral spinal cord. The most widely used small animal model in neurourological research is the rat. However, urodynamic studies suggest that, in sharp comparison to rat, guinea pig micturition is very similar to human micturition. Therefore, the present study, using retrograde and anterograde tracing and double immunofluorescence, was designed to investigate the location of Barrington''s nucleus in the guinea pig, to identify Barrington''s nucleus projections to the spinal cord and to clarify the relationship of Barrington''s nucleus to pontine noradrenergic cell groups. Results show that Barrington''s nucleus is located in the dorsolateral pons, projects to the intermediolateral and intermediomedial cell groups of the lumbosacral spinal cord and is clearly distinct from the pontine noradrenergic cell groups. These results show that the neuroanatomical circuitry in the spinal cord and brainstem that controls micturition in the guinea pig is similar to that in rat. This means that the differences between rat and guinea pig micturition on a behavioral level are not the result of different neuroanatomical connections in these parts of the central nervous system. These results provide a neuroanatomical basis for further neurourological studies in guinea pig. [Copyright &y& Elsevier]
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- 2007
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9. KV2.1 channels mediate hypoxic inhibition of IKV in native pulmonary arterial smooth muscle cells of the rat
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Hogg, Dayle S., Davies, Andrew R.L., McMurray, Gordon, and Kozlowski, Roland Z.
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PULMONARY artery , *POTASSIUM channels , *PULMONARY circulation - Abstract
Objective: To determine whether, in native pulmonary arterial smooth muscle cells (PASMC), KV2.1 delayed-rectifying K+ channels are central to the process of hypoxic pulmonary vasoconstriction. Methods: In this study, we tested for the presence of KV2.1 channel transcripts in rat small pulmonary arteries using RT-PCR, and for the protein itself using immunolocalisation. The contribution of KV2.1 channels to whole-cell KV currents (IKV) and their role in hypoxic inhibition of IKV in native PASMC was investigated utilising patch-clamp recordings. Results: KV2.1 mRNA expression and AbKV2.1 (anti-KV2.1 antibody) protein immunoreactivity were both present in small pulmonary arteries. Dialysis of PASMC with AbKV2.1 significantly attenuated IKV by 67% at +50 mV. Hypoxia (∼20–30 mmHg) inhibited IKV by ∼70% at +50 mV. Ablation of currents associated with KV2.1 using AbKV2.1 caused a marked reduction in the amplitude of IKV. Hypoxia in the presence of the antibody did not affect the magnitude of IKV. Conclusions: These results indicate that KV2.1 channel subunits exist within small pulmonary arteries and conduct a significant part of IKV within native PASMC. Furthermore, application of AbKV2.1 abolishes hypoxic inhibition of IKV in native PASMC suggesting that KV2.1 channels play a pivotal role in mediating hypoxic pulmonary vasoconstriction. [Copyright &y& Elsevier]
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- 2002
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10. Ca2+ channel properties in smooth muscle cells of the urinary bladder from pig and human
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Kajioka, Shunichi, Nakayama, Shinsuke, McMurray, Gordon, Abe, Kihachiro, and Brading, Alison F.
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CALCIUM channels , *SMOOTH muscle - Abstract
Ca2+ channel properties of pig and human bladder smooth muscle were investigated utilizing standard whole-cell patch clamp techniques. Both the amplitude obtained and the current density of Ca2+ channel current evoked by step depolarization were larger in human than in pig myocytes. The inward currents were sensitive to an L-type Ca2+ channel antagonist, nifedipine, the effects of which were not significantly different between species. In both species, prior application of ATP (0.1 mM) had no effect on activation of this voltage-sensitive channel current, while a muscarinic receptor agonist, carbachol (0.1 mM), significantly attenuated the amplitude of this current. Furthermore, inclusion of GDP-β-S or Heparin in the pipette abolished or had no effect on the suppression of Ca2+ current by carbachol, respectively. These results forward the pig as a good model for the human in detrusor Ca2+ channel properties, especially with regard to neural modulation, although voltage-sensitive Ca2+ channels seem to make greater contribution in human bladder physiology. [Copyright &y& Elsevier]
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- 2002
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11. THE RELATIVE IMPORTANCE OF ASSOCIATIVE STRATEGY AND MOTIVATION TO LEARN IN PAIRED-ASSOCIATE LEARNING.
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Duplessis, Gene, Hiscock, Merrill, and McMurray, Gordon A.
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PAIRED associate learning , *RECOLLECTION (Psychology) , *ACADEMIC motivation - Abstract
SUMMARY The study was designed to evaluate the relative contributions of mnemonic strategy and motivation to learn as facilitating influences in paired-associate learning. Sixty male and female undergraduates were asked to recall a list of 60 nouns under one of three motivation-to-learn conditions: (a) incidental learning, (b) intentional learning, and (c) intentional learning with incentive to learn. Within each motivation-to-learn condition, half of the Ss were provided an imaginal mnemonic strategy and half were given no mnemonic strategy. Mnemonic instructions had a markedly facilitative effect on performance, but there was no main effect for motivation to learn. However, there was a significant Mnemonic Instructions x Motivation to Learn interaction, which indicated that the motivation manipulations influenced recall only in the absence of mnemonic instructions. Motivational and strategic effects on learning were discussed in terms of a levels-of-processing framework. [ABSTRACT FROM AUTHOR]
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- 1981
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12. Residues W320 and Y328 within the binding site of the μ-opioid receptor influence opiate ligand bias.
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Hothersall, J. Daniel, Torella, Rubben, Humphreys, Sian, Hooley, Monique, Brown, Alastair, McMurray, Gordon, and Nickolls, Sarah A.
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BINDING sites , *LIGANDS (Biochemistry) , *OPIOID receptors , *THERAPEUTIC use of narcotics , *DRUG side effects - Abstract
The development of G protein-biased agonists for the μ-opioid receptor (MOR) offers a clear drug discovery rationale for improved analgesia and reduced side-effects of opiate pharmacotherapy. However, our understanding of the molecular mechanisms governing ligand bias is limited, which hinders our ability to rationally design biased compounds. We have investigated the role of MOR binding site residues W320 and Y328 in controlling bias, by receptor mutagenesis. The pharmacology of a panel of ligands in a cAMP and a β-arrestin2 assay were compared between the wildtype and mutated receptors, with bias factors calculated by operational analysis using ΔΔlog(τ/K A ) values. [ 3 H]diprenorphine competition binding was used to estimate affinity changes. Introducing the mutations W320A and Y328F caused changes in pathway bias, with different patterns of change between ligands. For example, DAMGO increased relative β-arrestin2 activity at the W320A mutant, whilst its β-arrestin2 response was completely lost at Y328F. In contrast, endomorphin-1 gained activity with Y328F but lost activity at W320A, in both pathways. For endomorphin-2 there was a directional shift from cAMP bias at the wildtype towards more β-arrestin2 bias at W320A. We also observe clear uncoupling between mutation-driven changes in function and binding affinity. These findings suggest that the mutations influenced the balance of pathway activation in a ligand-specific manner, thus identifying residues in the MOR binding pocket that govern ligand bias. This increases our understanding of how ligand/receptor binding interactions can be translated into agonist-specific pathway activation. [ABSTRACT FROM AUTHOR]
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- 2017
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13. Visceral and somatic pain modalities reveal NaV1.7-independent visceral nociceptive pathways.
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Hockley, James R. F., González‐Cano, Rafael, McMurray, Sheridan, Tejada‐Giraldez, Miguel A., McGuire, Cian, Torres, Antonio, Wilbrey, Anna L., Cibert‐Goton, Vincent, Nieto, Francisco R., Pitcher, Thomas, Knowles, Charles H., Baeyens, José Manuel, Wood, John N., Winchester, Wendy J., Bulmer, David C., Cendán, Cruz Miguel, and McMurray, Gordon
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VISCERAL pain , *SODIUM channels , *DELETION mutation , *CYCLOPHOSPHAMIDE , *MESSENGER RNA - Abstract
Key points Voltage-gated sodium channels play a fundamental role in determining neuronal excitability., Specifically, voltage-gated sodium channel subtype NaV1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown., Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling., These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics., Abstract Voltage-gated sodium channel NaV1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of NaV1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific NaV1.7 knockout mouse (NaV1.7Nav1.8) and selective small-molecule NaV1.7 antagonist PF-5198007. NaV1.7Nav1.8 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both NaV1.7Nav1.8 and littermate controls. Loss, or blockade, of NaV1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of NaV1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed NaV1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of NaV1.7 (in NaV1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV1.7 antagonist PF-5198007. Our data demonstrate that NaV1.7 (in NaV1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of NaV1.7 alone in the viscera may be insufficient in targeting chronic visceral pain. [ABSTRACT FROM AUTHOR]
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- 2017
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14. Genome-wide association analysis of pain severity in dysmenorrhea identifies association at chromosome 1p13.2, near the nerve growth factor locus.
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Jones, Amy V., Hockley, James R. F., Hyde, Craig, Gorman, Donal, Sredic-Rhodes, Ana, Bilsland, James, McMurray, Gordon, Furlotte, Nicholas A., Youna Hu, Hinds, David A., Cox, Peter J., Scollen, Serena, and Hu, Youna
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SINGLE nucleotide polymorphisms , *DISEASE susceptibility , *GENE expression , *DYSMENORRHEA , *PATIENTS , *DIAGNOSIS , *AGE distribution , *CHROMOSOMES , *GENETIC polymorphisms , *LONGITUDINAL method , *NERVE tissue proteins , *PAIN measurement , *SEQUENCE analysis - Abstract
Dysmenorrhea is a common chronic pelvic pain syndrome affecting women of childbearing potential. Family studies suggest that genetic background influences the severity of dysmenorrhea, but genetic predisposition and molecular mechanisms underlying dysmenorrhea are not understood. In this study, we conduct the first genome-wide association study to identify genetic factors associated with dysmenorrhea pain severity. A cohort of females of European descent (n = 11,891) aged 18 to 45 years rated their average dysmenorrhea pain severity. We used a linear regression model adjusting for age and body mass index, identifying one genome-wide significant (P < 5 × 10) association (rs7523086, P = 4.1 × 10, effect size 0.1 [95% confidence interval, 0.074-0.126]). This single nucleotide polymorphism is colocalising with NGF, encoding nerve growth factor. The presence of one risk allele corresponds to a predicted 0.1-point increase in pain intensity on a 4-point ordinal pain scale. The putative effects on NGF function and/or expression remain unknown. However, genetic variation colocalises with active epigenetic marks in fat and ovary tissues, and expression levels in aorta tissue of a noncoding RNA flanking NGF correlate. Participants reporting extreme dysmenorrhea pain were more likely to report being positive for endometriosis, polycystic ovarian syndrome, depression, and other psychiatric disorders. Our results indicate that dysmenorrhea pain severity is partly genetically determined. NGF already has an established role in chronic pain disorders, and our findings suggest that NGF may be an important mediator for gynaecological/pelvic pain in the viscera. [ABSTRACT FROM AUTHOR]
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- 2016
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15. The role of TRPM8 in the Guinea-pig bladder-cooling reflex investigated using a novel TRPM8 antagonist.
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Gardiner, Jennifer C., Kirkup, Anthony J., Curry, John, Humphreys, Sian, O’Regan, Paul, Postlethwaite, Michael, Young, Kimberley C., Kitching, Linda, Ethell, Brian T., Winpenny, David, and McMurray, Gordon
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TRP channels , *OVERACTIVE bladder , *MOLECULAR cloning , *CALCIUM ions , *GENE expression , *LABORATORY swine , *COMPARATIVE studies , *PATIENTS - Abstract
Patients with overactive bladder often exhibit abnormal bladder contractions in response to intravesical cold saline (positive ice-water test). The molecular entity involved in cold sensation within the urinary bladder is unknown, but a potential candidate is the ion channel, transient receptor potential (melastatin)-8 (TRPM8). The objective of the present study was to investigate the role of TRPM8 in a bladder-cooling reflex evoked in anaesthetised guinea-pigs that is comparable to the positive ice-water test seen in patients. Guinea-pig TRPM8 was cloned from L6 dorsal root ganglia (DRG) and expressed in HEK293 cells. Functional agonist- and cold-induced Ca 2+ influx and electrophysiology assays were performed in these cells, and for comparison in HEK293 cells expressing human TRPM8, using a novel TRPM8 antagonist, the S-enantiomer of 1-phenylethyl 4-(benzyloxy)-3-methoxybenzyl (2-aminoethyl) carbamate hydrochloride (PBMC). Potency data from these assays was used to calculate intravenous infusion protocols for targeted plasma concentrations of PBMC in studies on micturition reflexes evoked by intravesical infusion of menthol or cold saline in anaesthetised guinea-pigs. Tissue expression of TRPM8 in guinea-pig bladder, urethra and in dorsal root ganglia neurones traced from the bladder was also investigated. TRPM8 mRNA and protein were detected in L6 dorsal root ganglia, bladder urothelium and smooth muscle. PBMC antagonised in vitro activation of human and guinea-pig TRPM8 and reversed menthol and cold-induced facilitation of the micturition reflex at plasma concentrations consistent with in vitro potencies. The present data suggest that the bladder-cooling reflex in the guinea-pig involves TRPM8. The potential significance of TRPM8 in bladder disease states deserves future investigation. [ABSTRACT FROM AUTHOR]
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- 2014
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16. Co-Expression of GRK2 Reveals a Novel Conformational State of the µ-Opioid Receptor.
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Nickolls, Sarah A., Humphreys, Sian, Clark, Mellissa, and McMurray, Gordon
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G protein-coupled receptor kinases , *OPIOID receptors , *MOLECULAR interactions , *ANALGESICS , *LIGANDS (Biochemistry) , *MORPHINE , *GENE expression - Abstract
Agonists at the µ-opioid receptor are known to produce potent analgesic responses in the clinical setting, therefore, an increased understanding of the molecular interactions of ligands at this receptor could lead to improved analgesics. As historically morphine has been shown to be a poor recruiter of β-arrestin in recombinant cell systems and this can be overcome by the co-expression of GRK2, we investigated the effects of GRK2 co-expression, in a recombinant µ-opioid receptor cell line, on ligand affinity and intrinsic activity in both β-arrestin recruitment and [35S]GTPγS binding assays. We also investigated the effect of receptor depletion in the β-arrestin assay. GRK2 co-expression increased both agonist Emax and potency in the β-arrestin assay. The increase in agonist potency could not be reversed using receptor depletion, supporting that the effects were due to a novel receptor conformation not system amplification. We also observed a small but significant effect on agonist KL values. Potency values in the [35S]GTPγS assay were unchanged; however, inverse agonist activity became evident with GRK2 co-expression. We conclude that this is direct evidence that the µ-opioid receptor is an allosteric protein and the co-expression of signalling molecules elicits changes in its conformation and thus ligand affinity. This has implications when describing how ligands interact with the receptor and how efficacy is determined. [ABSTRACT FROM AUTHOR]
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- 2013
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17. Serendipity in drug-discovery: A new series of 2-(benzyloxy)benzamides as TRPM8 antagonists.
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Brown, Alan, Ellis, David, Favor, David A., Kirkup, Tony, Klute, Wolfgang, MacKenny, Malcolm, McMurray, Gordon, and Stennett, Adam
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SERENDIPITY , *DRUG development , *BENZAMIDE , *DRUG design , *CHEMICAL synthesis , *COMPARATIVE studies - Abstract
Abstract: A new series of 2-(benzyloxy)benzamides are presented that are potent functional antagonists of TRPM8 and possess improved LipE and LE compared to the original lead. They were discovered through a series of compound libraries and we present a powerful visualization method for the chemical space explored with each library. Remarkably this new series originated from the highest risk design strategy where compounds were synthesised with the least degree of similarity to the lead structure. [Copyright &y& Elsevier]
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- 2013
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18. The passive and active contractile properties of the neurogenic, underactive bladder.
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Young, John S., Johnston, Louise, Soubrane, Camille, McCloskey, Karen D., McMurray, Gordon, Eccles, Rachel, and Fry, Christopher H.
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BLADDER diseases , *URINARY organs , *NEUROGENIC bladder , *NEUROLOGIC manifestations of general diseases , *PATHOLOGY - Abstract
What's known on the subject? and What does the study add? Detrusor underactivity is highly prevalent, particularly in the elderly. It is assumed to result from detrusor failure, although detrusor contractility is often derived from urodynamics studies. Given that detrusor pressure and force are not proportional and urodynamics cannot identify the basis of the pathology, we produced a neurogenic animal model with a highly-compliant bladder and studied detrusor muscle properties, aiming to increase our understanding of the underlying pathology., Highly compliant bladders were characterized by reduced passive wall stiffness and stretched detrusor muscle strips exhibited an enhanced rate of relaxation. These detrusor strips displayed spontaneous contractions that were of greater amplitude (expressed as a ratio of bladder wall stiffness) than those of strips from sham-operated animals; spontaneous contractions increased in amplitude when stimulated by an agonist. These data imply that compliance is not the result of a reduction of detrusor contractility; we hypothesize that altered matrix properties reduce the magnitude with which force can be generated to void the bladder., Objective To characterize passive and active changes in detrusor activity in a highly compliant bladder., Materials and Methods Bladders from adult female Sprague- Dawley rats were used 5 weeks after lower thoracic ( T8) spinal cord transection or a sham-operation., Passive wall properties were assessed by pressure-volume relationships from whole bladders and the tensile response of bladder strips after a rapid (<0.5 s) stretch., Active properties were assessed from the frequency and amplitude of spontaneous contractions of bladder strips, and their response to the inotropic TRPV4 agonist GSK1016790A., Results Passive bladder wall stiffness of SCT bladders was significantly reduced compared to that of the sham-operated control group ( N = 6 and 8, respectively) and SCT bladder strips relaxed more quickly than those from sham-operated rats., The frequency of spontaneous contractions was reduced in SCT rats, and their amplitude, expressed as a ratio of bladder wall stiffness, was greater than in sham-operated rats., GSK1016790A (0.1 μM) significantly increased amplitude in strips from both sham-operated and SCT groups., Conclusions There is no evidence of contractile failure in a highly-compliant bladder. The observations of reduced passive bladder wall stiffness and an enhanced rate of stress relaxation lead to the conclusion that increased compliance is marked by altered matrix properties that dissipate muscle force, thereby generating low pressures., Contractile agonists may be effective for improving bladder function in detrusor underactivity. [ABSTRACT FROM AUTHOR]
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- 2013
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19. Identification of 5-HT2C mediated mechanisms involved in urethral sphincter reflexes in a guinea-pig model of urethral function.
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Conlon, Kelly, Miner, Wes, McCleary, Scott, and McMurray, Gordon
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URINARY incontinence treatment , *DRUG therapy , *DRUG dosage , *KIDNEY disease treatments , *DRUG administration , *GUINEA pigs as laboratory animals - Abstract
What's known on the subject? and What does the study add? Preclinically, studies investigating urethral function have shown that the clinical benefit of agents such as duloxetine may partly reflect increases in urethral striated muscle activity via a central mode of action. Duloxetine has been shown to inhibit the presynaptic reuptake of 5-HT and norepinephrine in Onuf's nucleus, leading to an increased activity of pudendal motor neurones and a subsequent increase in the strength of urethral sphincter contractions. Preclinical studies have postulated a role for both 5-HT2C receptors and 5-HT2A receptors in external urethral sphincter (EUS) function, with differences between species that may reflect the differing physiological roles of the EUS in different preclinical species. The present study therefore aimed to investigate the 5-HT receptor subtype involved in EUS function in the guinea-pig. The in vivo data reported in the present study suggest that the effects of clinical agents used to treat stress urinary incontinence, which enhance serotonergic drive, may be mediated, at least in part, via 5-HT2C receptors. OBJECTIVE To elucidate the subtype of 5-HT receptor involved in urethral function using a preclinical model of urethral function., MATERIALS AND METHODS The effects of the 5-HT2C agonist Ro 600-175 were investigated by measuring the urethral pressure profile in anaesthetized guinea-pigs together with antagonists at 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes., RESULTS Ro 600-175 increased peak urethral pressure in a dose-dependent manner, This effect was reversed by the selective 5-HT2C antagonist SB 242084, Neither the 5-HT2A antagonist MDL 100907, nor the 5-HT2B antagonist SB 240741 had any significant effect on the response., CONCLUSIONS The clinical benefit of drugs used to treat stress urinary incontinence through enhanced serotonergic and adrenergic drive may be mediated, at least in part, via 5-HT2C receptors, Selective 5-HT2C agonism increases urethral tone, and hence provides an opportunity for developing new pharmacotherapies for stress urinary incontinence with reduced side-effects. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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20. Kappa agonist CovX-Bodies
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Roberts, Lee R., Brady, Kevin, Brown, Amy, Davey, Doreen, Feng, Lijin, Huang, Hanhua, Liu, Dingguo, Malet, Laia, McMurray, Gordon, Phelan, Anne, Saunders, Ken, and Bhat, Abhijit
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PEPTIDES , *OPIOID receptors , *LYSINE , *IMMUNOGLOBULINS , *DRUG synergism , *AMINO acids - Abstract
Abstract: Small peptidic kappa agonists were covalently linked to the reactive lysine of the CovX antibody to create compounds having potent activity at the kappa receptor with greatly extended half-life when compared to the parent peptide as exemplified by compound 20. [Copyright &y& Elsevier]
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- 2012
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21. Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: Design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence
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Andrews, Mark D., Fish, Paul V., Blagg, Julian, Brabham, Tiffini K., Brennan, Paul E., Bridgeland, Alison, Brown, Alan D., Bungay, Peter J., Conlon, Kelly M., Edmunds, Nicholas J., af Forselles, Kerry, Gibbons, Colleen P., Green, Martin P., Hanton, Giles, Holbrook, Mark, Jessiman, Alan S., McIntosh, Karin, McMurray, Gordon, Nichols, Carly L., and Root, James A.
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AZEPINES , *SEROTONIN agonists , *URINARY incontinence treatment , *PHARMACOKINETICS , *DRUG design , *DRUG efficacy - Abstract
Abstract: New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT2C receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT2A or 5-HT2B receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection. [Copyright &y& Elsevier]
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- 2011
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22. A Comparison of the α2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain.
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Nickolls, Sarah, Mace, Hannah, Fish, Rebecca, Edye, Michelle, Gurrell, Rachel, Ivarsson, Magnus, Pitcher, Tom, Tanimoto-Mori, Sachi, Richardson, Denise, Sweatman, Catherine, Nicholson, Janet, Ward, Cameron, Jinks, John, Bell, Christine, Young, Kimberly, Rees, Huw, Moss, Andrew, Kinloch, Ross, and McMurray, Gordon
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ALLOSTERIC regulation , *GABA receptors , *DRUGS , *SPINAL cord , *ANALGESIA , *BENZODIAZEPINES , *PAIN management , *MILD cognitive impairment - Abstract
GABAA receptors containing α2/3 subunits are current targets in the battle to develop new pain medications, as they are expressed in the spinal cord where increasing inhibitory drive should result in analgesia. However, this approach is prone to a range of side effects including sedation, cognitive impairment, and abuse as a consequence of the widespread influence of GABA. The ability to make subtype selective low-efficacy benzodiazepine compounds, which potentiate the action of GABA at specific α subunits, has the potential to reduce this side effect profile. In this study, we have investigated the effects of themedium-efficacy positive allosteric modulator (PAM) L-838,417 and the low-efficacy PAM TPA023 in a number of preclinical inflammatory and neuropathic pain models.We conclude that either the higher level of efficacy at α2/3 or efficacy at α5 is required for compounds to have a significant analgesic effect in a range of models, and, therefore, although the side-effect profile of compounds can be reduced compared to typical benzodiazepines, it is unlikely that it can be completely eliminated. [ABSTRACT FROM AUTHOR]
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- 2011
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23. Design and synthesis of pyridazinone-based 5-HT2C agonists
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Allerton, Charlotte M.N., Andrews, Mark D., Blagg, Julian, Ellis, David, Evrard, Edel, Green, Martin P., Liu, Kevin K.-C., McMurray, Gordon, Ralph, Michael, Sanderson, Vivienne, Ward, Robin, and Watson, Lesa
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ORGANIC synthesis , *PYRIDAZINONES , *SEROTONIN , *NEURAL receptors , *URINARY stress incontinence , *DRUG efficacy , *CENTRAL nervous system - Abstract
Abstract: The SAR of a series of pyridazinone derived 5-HT2C agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT2C functional agonism and selectivity over 5-HT2A and 5-HT2B. This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration. [Copyright &y& Elsevier]
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- 2009
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24. Design and synthesis of piperazinylpyrimidinones as novel selective 5-HT2C agonists
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Andrews, Mark D., Green, Martin P., Allerton, Charlotte M.N., Batchelor, David V., Blagg, Julian, Brown, Alan D., Gordon, David W., McMurray, Gordon, Millns, Daniel J., Nichols, Carly L., and Watson, Lesa
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DRUG design , *DRUG development , *SEROTONIN agonists , *PYRIMIDINES , *MEDICAL model , *THERAPEUTICS ,TREATMENT of urinary stress incontinence - Abstract
Abstract: This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT2C agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT2A and 5-HT2B receptors. Compound 11 was active in in vivo models of stress urinary incontinence. [Copyright &y& Elsevier]
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- 2009
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25. Discovery of a novel azepine series of potent and selective 5-HT2C agonists as potential treatments for urinary incontinence
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Brennan, Paul E., Whitlock, Gavin A., Ho, Danny K.H., Conlon, Kelly, and McMurray, Gordon
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AZEPINES , *SEROTONIN agonists , *URINARY incontinence treatment , *ORGANIC synthesis , *CENTRAL nervous system , *DRUG efficacy , *THERAPEUTICS - Abstract
Abstract: A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT2C agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT2C agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT2B. Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence. [Copyright &y& Elsevier]
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- 2009
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26. Novel 2-imidazoles as potent, selective and CNS penetrant α1A adrenoceptor partial agonists
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Roberts, Lee R., Bryans, Justin, Conlon, Kelly, McMurray, Gordon, Stobie, Alan, and Whitlock, Gavin A.
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IMIDAZOLES , *CENTRAL nervous system , *ADRENERGIC receptors , *HETEROCYCLIC compounds , *SULFONES , *ETHERS , *PHARMACEUTICAL chemistry - Abstract
Abstract: A novel series of central nervous system (CNS) penetrant indane 2-imidazoles have been identified as potent, partial agonists of the α1A adrenergic receptor, having good selectivity over the α1B, α1D and α2 sub-types. A key structural motif to impart selectivity is a methylene spacer between the indane and a pendant substituent, which includes heterocycles, sulphones and ethers. Introduction of an ortho-halogen to this group led to a lowering of intrinsic efficacy (E max). [Copyright &y& Elsevier]
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- 2008
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27. Inward current oscillation underlying tonic contraction caused via ET[sub A] receptors in pig detrusor smooth muscle.
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Kajioka, Shunichi, Nakayama, Shinsuke, McCoy, Rachel, McMurray, Gordon, Abe, Kihachiro, and Brading, Alison F.
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BLADDER , *ENDOTHELINS , *SWINE , *SMOOTH muscle , *CALCIUM channels , *CHLORIDE channels - Abstract
Endothelin-I (ET-1) is a powerful vasoconstricting peptide. Recent studies showed synthesis of ET-1 and the presence of ET receptors in urinary bladder smooth muscle cells. In the present study, we investigated the possible role of ET-1 in detrusor contraction and its underlying mechanisms in terms of electrical activity. ET-1 caused dose-dependent tonic contraction of bladder smooth muscle strips. Whole cell patch-clamp experiments revealed that ET-1 induced a single transient inward current in the majority of detrusor cells and that additional inward current oscillations were induced in one-third of the cells. The inward current oscillation and tonic contraction shared several characteristic features: 1) both activities lasted for a considerable time after ET-1 washout and 2) only prior application of ET[sub A] receptor antagonists, not ET[sub B] receptor antagonists, significantly suppressed ET-1-induced contractions and the oscillating inward currents. It was concluded that the inward current oscillation underlies ET-1-induced tonic contraction. Experiments with ion substitution and channel blockers suggested that periodic activation of Ca[sup 2+]-activated Cl[sup -] channels caused the oscillating inward currents. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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