21 results on '"Prisinzano TE"'
Search Results
2. Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents.
- Author
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Kivell BM, Paton KF, Kumar N, Morani AS, Culverhouse A, Shepherd A, Welsh SA, Biggerstaff A, Crowley RS, and Prisinzano TE
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- Animals, Anxiety drug therapy, Anxiety metabolism, Cocaine-Related Disorders drug therapy, Diterpenes adverse effects, Diterpenes chemistry, Diterpenes, Clerodane adverse effects, Diterpenes, Clerodane chemistry, Learning drug effects, Male, Mesylates adverse effects, Mesylates chemistry, Mice, Motor Activity drug effects, Nociception drug effects, Pain drug therapy, Pain etiology, Pain metabolism, Rats, Recognition, Psychology drug effects, Behavior, Animal drug effects, Cocaine adverse effects, Cocaine-Related Disorders metabolism, Cocaine-Related Disorders psychology, Diterpenes pharmacology, Diterpenes, Clerodane pharmacology, Mesylates pharmacology, Receptors, Opioid, kappa agonists
- Abstract
The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum . We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 °C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.
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- 2018
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3. Modular Approach to pseudo-Neoclerodanes as Designer κ-Opioid Ligands.
- Author
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Sherwood AM, Williamson SE, Crowley RS, Abbott LM, Day VW, and Prisinzano TE
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- Diterpenes, Clerodane, Ligands, Molecular Structure, Receptors, Opioid, kappa, Diterpenes chemistry
- Abstract
Informed by previous semisynthetic work on salvinorin A, a modular total synthesis has been developed capable of producing novel compounds targeting the κ-opioid receptor. The strategy has permitted the deliberate simplification and introduction of functionality about the target molecule to provide access to molecular features on salvinorin A otherwise unattainable by semisynthesis. Using this approach, a potent pseudo-neoclerodane κ-opioid receptor ligand (2) has been realized.
- Published
- 2017
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4. Semisynthesis and Kappa-Opioid Receptor Activity of Derivatives of Columbin, a Furanolactone Diterpene.
- Author
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Yilmaz A, Crowley RS, Sherwood AM, and Prisinzano TE
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- Africa, Analgesics pharmacology, Animals, Diterpenes chemistry, Diterpenes, Clerodane pharmacology, Lactones chemistry, Ligands, Molecular Structure, Ranunculus chemistry, Structure-Activity Relationship, Tinospora chemistry, Diterpenes chemical synthesis, Diterpenes pharmacology, Diterpenes, Clerodane chemistry, Lactones chemical synthesis, Lactones pharmacology, Receptors, Opioid, kappa agonists
- Abstract
Columbin (1) is a furanolactone diterpene isolated from the roots of Jateorhiza and Tinospora species. These species generally grow in Asia and Africa and have been used in folk medicine for their apparent analgesic and antipyretic activities. Columbin (1) is of particular interest due to its structural similarity to the known kappa-opioid receptor (KOR) agonist salvinorin A. Given that the KOR is of interest in the study of many serious diseases, such as anxiety, depression, and drug addiction, obtaining natural or semisynthetic molecules with KOR activity recently has gained much interest. For this reason, in the present study, derivatives of 1 were designed and synthesized using known structure-activity relationships of salvinorin A at KORs. The structures of the columbin analogues prepared were elucidated by NMR spectroscopy and mass spectroscopy, and their KOR activity was investigated in vitro by inhibition of forskolin-induced cAMP accumulation. Slight improvements in KOR activity were observed in columbin derivatives over their parent compound. However, despite the structural similarities to salvinorin A, neither columbin (1) nor its derivatives were potent KOR ligands. This work represents not only the first evaluation of columbin (1) at the KOR but also one of the first works to explore synthetic strategies that are tolerated on the columbin core.
- Published
- 2017
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5. The analgesic and anti-inflammatory effects of Salvinorin A analogue β-tetrahydropyran Salvinorin B in mice.
- Author
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Paton KF, Kumar N, Crowley RS, Harper JL, Prisinzano TE, and Kivell BM
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- Animals, Diterpenes, Clerodane, Male, Mice, Analgesics therapeutic use, Anti-Inflammatory Agents therapeutic use, Diterpenes therapeutic use, Hyperalgesia drug therapy, Inflammation drug therapy, Neuralgia drug therapy, Receptors, Opioid, kappa agonists
- Abstract
Background: Drugs activating the mu opioid receptor are routinely used to treat severe acute and chronic pain. Unfortunately, side effects including nausea, constipation, respiratory depression, addiction and tolerance can limit clinical utility. In contrast, kappa opioid receptor (KOPr) agonists, such as Salvinorin A (SalA), have analgesic properties with little potential for abuse., Methods: We evaluated SalA and the novel analogue β-tetrahydropyran Salvinorin B (β-THP SalB) for the ability to modulate pain and inflammation in vivo. The hot water tail-withdrawal assay, intradermal formalin-induced inflammatory pain and paclitaxel-induced neuropathic pain models were used to evaluate analgesic properties in mice. Tissue infiltration of inflammatory cells was measured by histology and flow cytometry., Results: β-tetrahydropyran Salvinorin B produced a longer duration of action in the tail-withdrawal assay compared to the parent compound SalA, and, like SalA and U50,488, β-THP SalB is a full agonist at the KOPr. In the formalin-induced inflammatory pain model, β-THP SalB and SalA significantly reduced pain score, paw oedema and limited the infiltration of neutrophils into the inflamed tissue. β-THP SalB and SalA supressed both mechanical and cold allodynia in the paclitaxel-induced neuropathic pain model, in a dose-dependent manner., Conclusions: Structural modification of SalA at the C-2 position alters its analgesic potency and efficacy in vivo. Substitution with a tetrahydropyran group at C-2 produced potent analgesic and anti-inflammatory effects, including a reduction in paclitaxel-induced neuropathic pain. This study highlights the potential for KOPr agonists as analgesics with anti-inflammatory action and little risk of abuse., Significance: Salvinorin A and the novel analogue β-THP Salvinorin B show analgesic effects in the tail-withdrawal and formalin assays. They reduce oedema and decrease neutrophil infiltration into inflamed tissue, and suppress mechanical and cold allodynia in paclitaxel-induced neuropathic pain., (© 2017 European Pain Federation - EFIC®.)
- Published
- 2017
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6. Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone.
- Author
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Zhou Y, Crowley RS, Ben K, Prisinzano TE, and Kreek MJ
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- Alcoholism drug therapy, Animals, Central Nervous System Agents pharmacology, Diterpenes therapeutic use, Diterpenes, Clerodane, Drinking drug effects, Ethanol pharmacology, Female, Male, Mesylates therapeutic use, Mice, Naltrexone metabolism, Naltrexone pharmacokinetics, Narcotic Antagonists pharmacology, Receptors, Opioid, kappa agonists, Receptors, Opioid, mu antagonists & inhibitors, Alcohol Drinking drug therapy, Diterpenes metabolism, Diterpenes pharmacokinetics, Mesylates metabolism, Mesylates pharmacokinetics
- Abstract
Mesyl Salvinorin B (MSB) is a potent selective kappa opioid receptor (KOP-r) agonist that has potential for development as an anti-psychostimulant agent with fewer side-effects (e.g., sedation, depression and dysphoria) than classic KOP-r agonists. However, no such study has been done on alcohol. We investigated whether MSB alone or in combination with naltrexone (mu-opioid receptor antagonist) altered voluntary alcohol drinking in both male and female mice. Mice, subjected to 3weeks of chronic escalation drinking (CED) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We found that single, acute administration of MSB dose-dependently reduced alcohol intake and preference in mice after 3-week CED. The effect was specific to alcohol, as shown by the lack of any effect of MSB on sucrose or saccharin intake. We also used the drinking-in-the-dark (DID) model with limited access (4h/day) to evaluate the pharmacological effect of MSB after 3weeks of DID. However, MSB had no effect on alcohol drinking after 3-week DID. Upon investigation of potential synergistic effects between naltrexone and MSB, we found that acute administration of a combination of MSB and naltrexone reduced alcohol intake profoundly after 3-week CED at doses lower than those individual effective doses. Repeated administrations of this combination showed less tolerance development than repeated MSB alone. Our study suggests that the novel KOP-r agonist MSB both alone and in combination with naltrexone shows potential in alcoholism treatment models., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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7. Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability.
- Author
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Crowley RS, Riley AP, Sherwood AM, Groer CE, Shivaperumal N, Biscaia M, Paton K, Schneider S, Provasi D, Kivell BM, Filizola M, and Prisinzano TE
- Subjects
- Analgesics, Opioid chemical synthesis, Analgesics, Opioid chemistry, Animals, CHO Cells, Cells, Cultured, Cricetulus, Diterpenes chemical synthesis, Diterpenes chemistry, Diterpenes, Clerodane, Dose-Response Relationship, Drug, Male, Molecular Structure, Pain Measurement, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Analgesics, Opioid pharmacology, Diterpenes pharmacology, Pain drug therapy, Receptors, Opioid, mu agonists, Salvia chemistry
- Abstract
Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC
50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects.- Published
- 2016
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8. Pharmacology and anti-addiction effects of the novel κ opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A.
- Author
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Simonson B, Morani AS, Ewald AW, Walker L, Kumar N, Simpson D, Miller JH, Prisinzano TE, and Kivell BM
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- Animals, Behavior, Animal drug effects, Brain drug effects, Brain metabolism, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, Cocaine administration & dosage, Cocaine-Related Disorders metabolism, Diterpenes, Clerodane, Drug-Seeking Behavior drug effects, HEK293 Cells, Humans, MAP Kinase Signaling System drug effects, Male, Mice, Motor Activity drug effects, Pain drug therapy, Pain metabolism, Rats, Sprague-Dawley, Receptors, Opioid, kappa metabolism, Self Administration, Cocaine-Related Disorders drug therapy, Diterpenes pharmacology, Diterpenes therapeutic use, Dopamine Plasma Membrane Transport Proteins metabolism, Mesylates pharmacology, Mesylates therapeutic use, Receptors, Opioid, kappa agonists
- Abstract
Background and Purpose: Acute activation of κ opioid (KOP) receptors results in anticocaine-like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classic KOP receptor agonists, but with a different side effect profile., Experimental Approach: We evaluated the duration of effects of Mesyl Sal B in vivo utilizing antinociception assays and screened for cocaine-prime induced cocaine-seeking behaviour in self-administering rats to predict anti-addiction effects. Cellular transporter uptake assays and in vitro voltammetry were used to assess modulation of dopamine transporter (DAT) function and to investigate transporter trafficking and kinase signalling pathways modulated by KOP receptor agonists., Key Results: Mesyl Sal B had a longer duration of action than SalA, had anti-addiction properties and increased DAT function in vitro in a KOP receptor-dependent and Pertussis toxin-sensitive manner. These effects on DAT function required ERK1/2 activation. We identified differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering cell-surface expression of DAT., Conclusions and Implications: SalA analogues, such as Mesyl Sal B, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin-based neoclerodane diterpene KOP receptor ligands produce both anti-addiction and adverse side effects., Linked Articles: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2., (© 2014 The British Pharmacological Society.)
- Published
- 2015
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9. Neoclerodanes as atypical opioid receptor ligands.
- Author
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Prisinzano TE
- Subjects
- Animals, Diterpenes chemistry, Diterpenes, Clerodane chemistry, Diterpenes, Clerodane metabolism, Furans chemistry, Furans metabolism, Humans, Ligands, Pyrones chemistry, Pyrones metabolism, Diterpenes metabolism, Drug Discovery methods, Receptors, Opioid metabolism
- Abstract
The neoclerodane diterpene salvinorin A is the major active component of the hallucinogenic mint plant Salvia divinorum Epling and Játiva (Lamiaceae). Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of opioid receptors, the site of action of morphine and related analogues, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable because (1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist and (2) its effects are not mediated through the previously investigated targets of psychotomimetics. This Perspective outlines our research program, illustrating a new direction to the development of tools to further elucidate the biological mechanisms of drug tolerance and dependence. The information gained from these efforts is expected to facilitate the design of novel agents to treat pain, drug abuse, and other central nervous system disorders.
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- 2013
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10. Semisynthetic neoclerodanes as kappa opioid receptor probes.
- Author
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Lovell KM, Vasiljevik T, Araya JJ, Lozama A, Prevatt-Smith KM, Day VW, Dersch CM, Rothman RB, Butelman ER, Kreek MJ, and Prisinzano TE
- Subjects
- Animals, Biomarkers blood, Diterpenes chemical synthesis, Diterpenes pharmacology, Diterpenes, Clerodane chemical synthesis, Diterpenes, Clerodane chemistry, Diterpenes, Clerodane pharmacology, Humans, Macaca mulatta, Male, Microwaves, Neurons drug effects, Neurons metabolism, Protein Binding, Receptors, Opioid, kappa metabolism, Salvia chemistry, Structure-Activity Relationship, Diterpenes chemistry, Receptors, Opioid, kappa chemistry
- Abstract
Modification of the furan ring of salvinorin A (1), the main active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. Conversion of the furan ring to an aldehyde at the C-12 position (5) has allowed for the synthesis of analogues with new carbon-carbon bonds at that position. Previous methods for forming these bonds, such as Grignard and Stille conditions, have met with limited success. We report a palladium catalyzed Liebeskind-Srogl cross-coupling reaction of a thioester and a boronic acid that occurs at neutral pH and ambient temperature to produce ketone analogs at C-12. To the best of our knowledge, this is the first reported usage of the Liebeskind-Srogl reaction to diversify a natural product scaffold. We also describe a one-step protocol for the conversion of 1 to 12-epi-1 (3) through microwave irradiation. Previously, this synthetically challenging process has required multiple steps. Additionally, we report in this study that alkene 9 and aromatic analogues 12, 19, 23, 25, and 26 were discovered to retain affinity and selectivity at kappa opioid receptors (KOP). Finally, we report that the furan-2-yl analog of 1 (31) has similar affinity to 1. Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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11. Herkinorin analogues with differential beta-arrestin-2 interactions.
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Tidgewell K, Groer CE, Harding WW, Lozama A, Schmidt M, Marquam A, Hiemstra J, Partilla JS, Dersch CM, Rothman RB, Bohn LM, and Prisinzano TE
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- Cell Line, Diterpenes chemistry, Diterpenes, Clerodane, Humans, Magnetic Resonance Spectroscopy, Mass Spectrometry, Radioligand Assay, Receptors, Opioid, kappa agonists, Receptors, Opioid, mu agonists, beta-Arrestin 2, beta-Arrestins, Arrestins chemistry, Diterpenes pharmacology
- Abstract
Salvinorin A is a psychoactive natural product that has been found to be a potent and selective kappa opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent kappa opioid receptor signaling yet leads to less receptor downregulation than observed with other kappa agonists. Our initial chemical modifications of salvinorin A have yielded one analogue, herkinorin ( 1c), with high affinity at the microOR. We recently reported that 1c does not promote the recruitment of beta-arrestin-2 to the microOR or receptor internalization. Here we describe three new derivatives of 1c ( 3c, 3f, and 3i) with similar properties and one, benzamide 7b, that promotes recruitment of beta-arrestin-2 to the microOR and receptor internalization. When the important role micro opioid receptor regulation plays in determining physiological responsiveness to opioid narcotics is considered, micro opioids derived from salvinorin A may offer a unique template for the development of functionally selective mu opioid receptor-ligands with the ability to produce analgesia while limiting adverse side effects.
- Published
- 2008
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12. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: exploration of the 1-position.
- Author
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Holden KG, Tidgewell K, Marquam A, Rothman RB, Navarro H, and Prisinzano TE
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- Binding, Competitive drug effects, Diterpenes chemistry, Diterpenes pharmacology, Diterpenes, Clerodane chemistry, Diterpenes, Clerodane pharmacology, Drug Evaluation, Preclinical, Furans chemistry, Furans pharmacology, Humans, Molecular Structure, Pyrones chemistry, Pyrones pharmacology, Receptors, Opioid, mu agonists, Receptors, Opioid, mu genetics, Recombinant Proteins agonists, Recombinant Proteins antagonists & inhibitors, Recombinant Proteins genetics, Structure-Activity Relationship, Diterpenes chemical synthesis, Diterpenes, Clerodane chemical synthesis, Furans chemical synthesis, Pyrones chemical synthesis, Receptors, Opioid, mu antagonists & inhibitors, Salvia chemistry
- Abstract
Modification of the C-1 ketone of salvinorin A (2a) produces analogues with opioid antagonist properties. Of particular significance is the finding that 1-deoxo-1,10-dehydrosalvinorin A (11a) is a moderately potent antagonist at all three opioid receptor subtypes, and that herkinorin (2b), a mu agonist, is converted to a weak antagonist by removal of the C-1 ketone (3b and 11b). These observations suggest that the ketone of 2b is a key structural feature responsible for mu agonist activity.
- Published
- 2007
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13. Salvinorin A: allosteric interactions at the mu-opioid receptor.
- Author
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Rothman RB, Murphy DL, Xu H, Godin JA, Dersch CM, Partilla JS, Tidgewell K, Schmidt M, and Prisinzano TE
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- Allosteric Regulation, Animals, CHO Cells, Cricetinae, Cricetulus, Cyclic AMP biosynthesis, Diprenorphine metabolism, Diterpenes, Clerodane, Enkephalin, Ala(2)-MePhe(4)-Gly(5)- metabolism, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Humans, Kinetics, Morphinans metabolism, Receptors, Opioid, mu metabolism, Diterpenes pharmacology, Receptors, Opioid, kappa agonists, Receptors, Opioid, mu drug effects
- Abstract
Salvinorin A [(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(3-furanyl)-dodecahydro-6a,10b-dimethyl-4,10-dioxo-2h-naphtho[2,1-c]pyran-7-carboxylic acid methyl ester] is a hallucinogenic kappa-opioid receptor agonist that lacks the usual basic nitrogen atom present in other known opioid ligands. Our first published studies indicated that Salvinorin A weakly inhibited mu-receptor binding, and subsequent experiments revealed that Salvinorin A partially inhibited mu-receptor binding. Therefore, we hypothesized that Salvinorin A allosterically modulates mu-receptor binding. To test this hypothesis, we used Chinese hamster ovary cells expressing the cloned human opioid receptor. Salvinorin A partially inhibited [(3)H]Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) (0.5, 2.0, and 8.0 nM) binding with E(MAX) values of 78.6, 72.1, and 45.7%, respectively, and EC(50) values of 955, 1124, and 4527 nM, respectively. Salvinorin A also partially inhibited [(3)H]diprenorphine (0.02, 0.1, and 0.5 nM) binding with E(MAX) values of 86.2, 64, and 33.6%, respectively, and EC(50) values of 1231, 866, and 3078 nM, respectively. Saturation binding studies with [(3)H]DAMGO showed that Salvinorin A (10 and 30 microM) decreased the mu-receptor B(max) and increased the K(d) in a dose-dependent nonlinear manner. Saturation binding studies with [(3)H]diprenorphine showed that Salvinorin A (10 and 40 microM) decreased the mu-receptor B(max) and increased the K(d) in a dose-dependent nonlinear manner. Similar findings were observed in rat brain with [(3)H]DAMGO. Kinetic experiments demonstrated that Salvinorin A altered the dissociation kinetics of both [(3)H]DAMGO and [(3)H]diprenorphine binding to mu receptors. Furthermore, Salvinorin A acted as an uncompetitive inhibitor of DAMGO-stimulated guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding. Viewed collectively, these data support the hypothesis that Salvinorin A allosterically modulates the mu-opioid receptor.
- Published
- 2007
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14. Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans.
- Author
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Butelman ER, Mandau M, Tidgewell K, Prisinzano TE, Yuferov V, and Kreek MJ
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- Amino Acid Sequence, Animals, Benzeneacetamides pharmacology, Biomarkers, Cloning, Molecular, Diterpenes, Clerodane, Female, Humans, Macaca mulatta, Male, Molecular Sequence Data, Naltrexone analogs & derivatives, Naltrexone pharmacology, Pyrrolidines pharmacology, Receptors, Opioid, kappa agonists, Receptors, Opioid, kappa chemistry, Sex Characteristics, Diterpenes pharmacology, Hallucinogens pharmacology, Prolactin blood, Receptors, Opioid, kappa genetics
- Abstract
This study focused on the in vivo effects of the kappa-opioid hallucinogen salvinorin A, derived from the plant Salvia divinorum. The effects of salvinorin A (0.0032-0.056 mg/kg i.v.) were studied in a neuroendocrine biomarker assay of the anterior pituitary hormone prolactin in gonadally intact, adult male and female rhesus monkeys (n = 4 each). Salvinorin A produced dose- and time-dependent neuroendocrine effects, similar to the synthetic high-efficacy kappa-agonist U69,593 ((+)-(5alpha,7 alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiniyl)-1-oxaspiro[4.5]dec-8yl]-benzeneacetamide), but of shorter duration than the latter. Salvinorin A was approximately equipotent to U69,593 in this endpoint (salvinorin A ED50, 0.015 mg/kg; U69,593 ED(50), 0.0098 mg/kg). The effects of i.v. salvinorin A were not prevented by a small dose of the opioid antagonist nalmefene (0.01 mg/kg s.c.) but were prevented by a larger dose of nalmefene (0.1 mg/kg); the latter nalmefene dose is sufficient to produce kappa-antagonist effects in this species. In contrast, the 5HT2 receptor antagonist ketanserin (0.1 mg/kg i.m.) did not prevent the effects of salvinorin A. As expected, the neuroendocrine effects of salvinorin A (0.0032 mg/kg i.v.) were more robust in female than in male subjects. Related studies focused on full-length cloning of the coding region of the rhesus monkey kappa-opioid receptor (OPRK1) gene and revealed a high homology of the nonhuman primate OPRK1 gene compared with the human OPRK1 gene, including particular C-terminal residues thought to be involved in receptor desensitization and internalization. The present studies indicate that the hallucinogen salvinorin A acts as a high-efficacy kappa-agonist in nonhuman primates in a translationally viable neuroendocrine biomarker assay.
- Published
- 2007
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15. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: selective modification of the furan ring.
- Author
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Harding WW, Schmidt M, Tidgewell K, Kannan P, Holden KG, Dersch CM, Rothman RB, and Prisinzano TE
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- Animals, CHO Cells, Cricetinae, DNA genetics, Diterpenes chemistry, Diterpenes pharmacology, Diterpenes, Clerodane, Humans, Ligands, Molecular Structure, Receptors, Opioid metabolism, Receptors, Opioid, kappa metabolism, Structure-Activity Relationship, Diterpenes chemical synthesis, Furans chemistry, Salvia chemistry
- Abstract
A synthetic sequence has been developed to selectively functionalize the furan ring of the natural product salvinorin A (2a). The synthetic routes described convert the furan ring in 2a into an N-sulfonylpyrrole, oxazole or an oxadiazole. In addition, a procedure has been found to remove the furan skeleton completely. Biological results indicate that replacement of the furan ring with an N-sulfonylpyrrole leads to reduced affinity and efficacy at kappa opioid receptors.
- Published
- 2006
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16. Synthesis of salvinorin A analogues as opioid receptor probes.
- Author
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Tidgewell K, Harding WW, Lozama A, Cobb H, Shah K, Kannan P, Dersch CM, Parrish D, Deschamps JR, Rothman RB, and Prisinzano TE
- Subjects
- Crystallography, X-Ray, Diterpenes, Clerodane, Molecular Conformation, Molecular Structure, Structure-Activity Relationship, Diterpenes chemical synthesis, Diterpenes chemistry, Diterpenes pharmacology, Plants, Medicinal chemistry, Receptors, Opioid agonists, Salvia chemistry
- Abstract
Several neoclerodanes, such as salvinorin A (1) and herkinorin (3), have recently been shown to possess opioid receptor activity in vitro and in vivo. To explore the structure-affinity relationships of this interesting class of compounds, we have synthesized a series of analogues from 1 isolated from Salvia divinorum. Here, we report the semisynthesis of neoclerodane diterpenes and their structure-affinity relationships at opioid receptors. This work will allow the further development of novel opioid receptor ligands.
- Published
- 2006
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17. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A.
- Author
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Harding WW, Schmidt M, Tidgewell K, Kannan P, Holden KG, Gilmour B, Navarro H, Rothman RB, and Prisinzano TE
- Subjects
- Humans, Molecular Structure, Receptors, Opioid, mu antagonists & inhibitors, Stereoisomerism, Diterpenes chemical synthesis, Diterpenes chemistry, Diterpenes pharmacology, Diterpenes, Clerodane chemical synthesis, Diterpenes, Clerodane chemistry, Diterpenes, Clerodane pharmacology, Plants, Medicinal chemistry, Receptors, Opioid, delta antagonists & inhibitors, Salvia chemistry
- Abstract
Salvinorin A (1) is a hallucinogenic neoclerodane diterpene isolated from the widely available psychoactive plant Salvia divinorum and is the first example of a non-nitrogenous opioid receptor ligand. At present, there is little information available as to why this compound is selective for kappa opioid receptors. One approach to better understanding the mode of binding of 1 at kappa receptors is to systematically alter the structure of 1 and examine the effects on opioid receptor affinity and activity. Currently, there is a paucity of methods described for the preparation of analogues derived from 1. Here, we report the investigation of several chemical transformations of 1 isolated from S. divinorum. In particular, this work provides a semisynthesis of salvinicins A (2) and B (3) and has identified 10a as the first neoclerodane diterpene with delta opioid antagonist activity.
- Published
- 2006
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18. Pharmacokinetics of the plant-derived kappa-opioid hallucinogen salvinorin A in nonhuman primates.
- Author
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Schmidt MD, Schmidt MS, Butelman ER, Harding WW, Tidgewell K, Murry DJ, Kreek MJ, and Prisinzano TE
- Subjects
- Animals, Brain drug effects, Brain metabolism, Diterpenes administration & dosage, Diterpenes blood, Diterpenes, Clerodane, Female, Hallucinogens administration & dosage, Hallucinogens blood, Hypnotics and Sedatives administration & dosage, Hypnotics and Sedatives blood, Hypnotics and Sedatives pharmacokinetics, Injections, Intravenous, Macaca mulatta, Male, Metabolic Clearance Rate physiology, Narcotics blood, Narcotics pharmacokinetics, Receptors, Opioid, kappa metabolism, Sex Characteristics, Time Factors, Diterpenes pharmacokinetics, Hallucinogens pharmacokinetics, Receptors, Opioid, kappa agonists
- Abstract
Salvinorin A, a potent hallucinogen isolated from the leaves of Salvia divinorum, has gained popularity among adolescents in the USA. No detailed study of the pharmacokinetics has been conducted in vivo. The present study investigates the in vivo pharmacokinetics of salvinorin A (0.032 mg/kg, i.v. bolus) in rhesus monkeys (n=4, 2 male, 2 female). The elimination t(1/2) was rapid (56.6+/-24.8 min) for all subjects. Pharmacokinetic differences (distribution t(1/2), elimination t(1/2), and AUC) were observed between males and females, suggesting potential sex differences in its pharmacologic effects. Salvinorin B, the presumed major metabolite, is observed to accumulate ex vivo; however, in this study it never reached the limit of detection., (Synapse 58:208-210, 2005. (c) 2005 Wiley-Liss, Inc.)
- Published
- 2005
- Full Text
- View/download PDF
19. Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands.
- Author
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Harding WW, Tidgewell K, Byrd N, Cobb H, Dersch CM, Butelman ER, Rothman RB, and Prisinzano TE
- Subjects
- Animals, CHO Cells, Cricetinae, Cricetulus, Diterpenes chemistry, Diterpenes pharmacology, Diterpenes, Clerodane, Furans chemistry, Furans pharmacology, Humans, Ligands, Pyrones chemistry, Pyrones pharmacology, Radioligand Assay, Receptors, Opioid, delta metabolism, Receptors, Opioid, kappa metabolism, Salvia, Stereoisomerism, Structure-Activity Relationship, Diterpenes chemical synthesis, Furans chemical synthesis, Pyrones chemical synthesis, Receptors, Opioid, mu agonists
- Abstract
Structural modification of salvinorin A, the active component of Salvia divinorum, has resulted in the synthesis of novel neoclerodane diterpenes with opioid receptor affinity and activity. We report in this study a nonnitrogenous neoclerodane diterpene with mu opioid receptor affinity (13) that is an agonist at mu opioid receptors. This represents the identification of a novel structural class of mu opioid receptor agonists.
- Published
- 2005
- Full Text
- View/download PDF
20. Determination of Salvinorin A in body fluids by high performance liquid chromatography-atmospheric pressure chemical ionization.
- Author
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Schmidt MS, Prisinzano TE, Tidgewell K, Harding W, Butelman ER, Kreek MJ, and Murry DJ
- Subjects
- Animals, Diterpenes blood, Diterpenes cerebrospinal fluid, Diterpenes urine, Diterpenes, Clerodane, Hallucinogens analysis, Humans, Macaca mulatta, Receptors, Opioid, kappa agonists, Reproducibility of Results, Sensitivity and Specificity, Chromatography, High Pressure Liquid methods, Diterpenes analysis
- Abstract
Salvinorin A was quantitated in human and rhesus monkey plasma, rhesus monkey cerebrospinal fluid, and human urine by negative ion LC-MS/APCI. The method for Salvinorin A has been fully validated, the LLOQ using FDA guidelines is 2 ng/mL for 0.5 mL plasma samples. The linear range was from 2 to 1000 ng/mL. Several derivatives in the Salvinorin family can also be analyzed by this method; d(3)-Salvinorin A was prepared and used as internal standard. The metabolite Salvinorin B can be semi quantitatively determined. The method has been used to establish that Salvinorin B is the principal metabolite of Salvinorin A ex vivo and to establish the analytical method to study in vivo samples.
- Published
- 2005
- Full Text
- View/download PDF
21. A facile method for the preparation of deuterium labeled salvinorin A: synthesis of [2,2,2-2H3]-salvinorin A.
- Author
-
Tidgewell K, Harding WW, Schmidt M, Holden KG, Murry DJ, and Prisinzano TE
- Subjects
- Body Fluids chemistry, Chromatography, Liquid, Deuterium, Diterpenes blood, Diterpenes isolation & purification, Diterpenes, Clerodane, Hallucinogens blood, Hallucinogens chemistry, Hallucinogens isolation & purification, Humans, Mass Spectrometry, Plant Extracts chemistry, Plant Leaves chemistry, Substance Abuse Detection methods, Diterpenes chemistry
- Abstract
Salvinorin A is a novel hallucinogen isolated from the widely available leaves of Salvia divinorum. Based on its mechanism of action, salvinorin A has shown potential as a stimulant abuse therapeutic. However, there are no methods for the detection of salvinorin A or its metabolites in biological fluids. In order to begin developing salvinorin A as a potential therapeutic, an understanding of its metabolism is needed. Here, a straightforward synthesis of a deuterium labeled analog of salvinorin A and its utility as an internal standard for the detection of salvinorin A and its metabolites in biological fluids by LC-MS is described.
- Published
- 2004
- Full Text
- View/download PDF
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