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Studies toward the pharmacophore of salvinorin A, a potent kappa opioid receptor agonist.

ABSTRACT: Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors.

SUBMITTER: Munro TA

PROVIDER: S-EPMC2777653 | biostudies-literature | 2005 Jan

REPOSITORIES: biostudies-literature

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Studies toward the pharmacophore of salvinorin A, a potent kappa opioid receptor agonist.

Munro Thomas A TA Rizzacasa Mark A MA Roth Bryan L BL Toth Beth A BA Yan Feng F

Journal of medicinal chemistry 20050101 2

Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors. ...[more]

PMID: 15658846

Similar Datasets

Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist.

Project description:Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited (3)H-bremazocine binding to cloned kappa opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent kappa opioid agonist at cloned kappa opioid receptors expressed in human embryonic kidney-293 cells and at native kappa opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT(2A) serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for kappa opioid receptors, kappa opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that kappa opioid receptors play a prominent role in the modulation of human perception.

| S-EPMC129372 | biostudies-literature

Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands.

Project description:Salvinorin A, the active ingredient of the hallucinogenic plant Salvia divinorum is the most potent known naturally occurring hallucinogen and is a selective ?-opioid receptor agonist. To better understand the ligand-receptor interactions, a series of dicarboxylic ester-type of salvinorin A derivatives were synthesized and evaluated for their binding affinity at ?-, ?- and ?-opioid receptors. Most of the analogues show high affinity to the ?-opioid receptor. Methyl malonyl derivative 4 shows the highest binding affinity (Ki=2nM), analogues 5, 7, and 14 exhibit significant affinity for the ?-receptor (Ki=21, 36 and 39nM).

| S-EPMC3651692 | biostudies-literature

Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability.

Project description:Previous structure-activity studies on the neoclerodane diterpenoid salvinorin A have demonstrated the importance of the acetoxy functionality on the A-ring in its activity as a ?-opioid receptor agonist. Few studies have focused on understanding the role of conformation in these interactions. Herein we describe the synthesis and evaluation of both flexible and conformationally restricted compounds derived from salvinorin A. One such compound, spirobutyrolactone 14, was synthesized in a single step from salvinorin B and had similar potency and selectivity to salvinorin A (EC50 = 0.6 ± 0.2 nM at ?; >10000 nM at ? and ?). Microsomal stability studies demonstrated that 14 was more metabolically resistant than salvinorin A. Evaluation of analgesic and anti-inflammatory properties revealed similar in vivo effects between 14 and salvinorin A. To our knowledge, this study represents the first example of bioisosteric replacement of an acetate group by a spirobutyrolactone to produce a metabolically resistant derivative.

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A review of salvinorin analogs and their kappa-opioid receptor activity.

Project description:The plant metabolite salvinorin A potently and selectively agonizes the human kappa-opioid receptor, an emerging target for next-generation analgesics. Here we review analogs of the salvinorin chemotype and their effects on selectivity, affinity and potency. Extensive peripheral modifications using isolated salvinorin A have delivered a trove of SAR information. More deep-seated changes are now possible by advances in chemical synthesis.

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Modification of the furan ring of salvinorin A: identification of a selective partial agonist at the kappa opioid receptor.

Project description:In an effort to find novel agents which selectively target the kappa opioid receptor (KOPR), we modified the furan ring of the highly potent and selective KOPR agonist salvinorin A. Introduction of small substituents at C-16 was well tolerated. 12-epi-Salvinorin A, synthesized in four steps from salvinorin A, was a selective partial agonist at the KOPR. No clear SAR patterns were observed for C-13 aryl ketones. Introducing a hydroxymethylene group between C-12 and the furan ring was tolerated. Small C-13 esters and ethers gave weak KOPR agonists, while all C-13 amides were inactive. Finally, substitution of oxadiazoles for the furan ring abolished affinity for the KOPR. None of the compounds displayed any KOPR antagonism or any affinity for mu or delta opioid receptors.

| S-EPMC2680211 | biostudies-literature

8-epi-Salvinorin B: crystal structure and affinity at the kappa opioid receptor.

Project description:There have been many reports of epimerization of salvinorins at C-8 under basic conditions, but little evidence has been presented to establish the structure of these compounds. We report here the first crystal structure of an 8-epi-salvinorin or derivative: the title compound, 2b. The lactone adopts a boat conformation with the furan equatorial. Several lines of evidence suggest that epimerization proceeds via enolization of the lactone rather than a previously proposed indirect mechanism. Consistent with the general trend in related compounds, the title compound showed lower affinity at the kappa opioid receptor than the natural epimer salvinorin B (2a). The related 8-epi-acid 4b showed no affinity.

| S-EPMC1805503 | biostudies-literature

Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens.

Project description:Kappa opioid receptors (KORs) have been implicated in depressive-like states associated with chronic administration of drugs of abuse and stress. Although KOR agonists decrease dopamine in the nucleus accumbens (NAc), KOR modulation of phasic dopamine release in the core and shell subregions of the NAc-which have distinct roles in reward processing-remains poorly understood.Studies were designed to examine whether the time course of effects of KOR activation on phasic dopamine release in the NAc core or shell are similar to effects on motivated behavior.The effect of systemic administration of the KOR agonist salvinorin A (salvA)-at a dose (2.0 mg/kg) previously determined to have depressive-like effects-was measured on electrically evoked phasic dopamine release in the NAc core or shell of awake and behaving rats using fast scan cyclic voltammetry. In parallel, the effects of salvA on intracranial self-stimulation (ICSS) and sucrose-reinforced responding were assessed. For comparison, a threshold dose of salvA (0.25 mg/kg) was also tested.The active, but not threshold, dose of salvA significantly decreased phasic dopamine release without affecting dopamine reuptake in the NAc core and shell. SalvA increased ICSS thresholds and significantly lowered breakpoint on the progressive ratio schedule, indicating a decrease in motivation. The time course of the KOR-mediated decrease in dopamine in the core was qualitatively similar to the effects on motivated behavior.These data suggest that the effects of KOR activation on motivation are due, in part, to inhibition of phasic dopamine signaling in the NAc core.

| S-EPMC2894632 | biostudies-literature

Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone.

Project description: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.

| S-EPMC5398281 | biostudies-literature

Orvinols with mixed kappa/mu opioid receptor agonist activity.

Project description:Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [(35)S]GTP?S assay are predictive of the in vivo profile.

| S-EPMC3646402 | biostudies-literature

The Kappa Opioid Receptor and the Sleep of Reason: Cortico-Subcortical Imbalance Following Salvinorin-A.

Project description:BackgroundThe mechanisms through which kappa opioid receptor (KOR) agonists induce psychotomimetic effects are largely unknown, although the modulation of this receptor has attracted attention for its clinical use. In this work, we characterize the neuropharmacological effects of salvinorin-A, a highly selective KOR agonist.MethodsChanges in multimodal electroencephalography, single-photon emission computed tomography, and subjective effects following the acute administration of salvinorin-A are reported. The study included 2 sub-studies that employed a double-blind, crossover, randomized, placebo-controlled design.ResultsThe electroencephalography measures showed a marked increase in delta and gamma waves and a decrease in alpha waves while subjects were under the effect of salvinorin-A. Regarding single-photon emission computed tomography measures, significant decreases in regional cerebral blood flow were detected in multiple regions of the frontal, temporal, parietal, and occipital cortices. Significant regional cerebral blood flow increases were observed in some regions of the medial temporal lobe, including the amygdala, the hippocampal gyrus, and the cerebellum. The pattern of subjective effects induced by salvinorin-A was similar to those observed in relation to other psychotomimetic drugs but with an evidently dissociative nature. No dysphoric effects were reported.ConclusionThe salvinorin-A-mediated KOR agonism induced dramatic psychotomimetic effects along with a generalized decrease in cerebral blood flow and electric activity within the cerebral cortex.

| S-EPMC8756086 | biostudies-literature

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