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.
Subject(s)
Diterpenes, Clerodane/chemical synthesis , Diterpenes/chemical synthesis , Furans/chemical synthesis , Pyrones/chemical synthesis , Receptors, Opioid, mu/antagonists & inhibitors , Salvia/chemistry , 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 RelationshipABSTRACT
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.
Subject(s)
Diterpenes/chemical synthesis , Furans/chemistry , Salvia/chemistry , 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 RelationshipABSTRACT
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.
Subject(s)
Diterpenes, Clerodane , Diterpenes , Plants, Medicinal/chemistry , Receptors, Opioid, delta/antagonists & inhibitors , Salvia/chemistry , Diterpenes/chemical synthesis , Diterpenes/chemistry , Diterpenes/pharmacology , Diterpenes, Clerodane/chemical synthesis , Diterpenes, Clerodane/chemistry , Diterpenes, Clerodane/pharmacology , Humans , Molecular Structure , Receptors, Opioid, mu/antagonists & inhibitors , StereoisomerismABSTRACT
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.
Subject(s)
Diterpenes/chemistry , 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/methodsABSTRACT
The synthesis of a chiral pilocarpine analogue 3 in which the lactone ring is replaced by an oxazolidinone and the bridging methylene group is in the ketone oxidation state has been accomplished. The utility of this compound as a key intermediate for the preparation of more complex structures was demonstrated by its reduction to two alcohol epimers and its reaction with a methylene ylide.
