The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and ß-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects.

RATIONALE: Kappa-opioid receptor (KOPr) agonists have pre-clinical anti-cocaine and analgesic effects. However, side effects including sedation, dysphoria, aversion, anxiety and depression limit their therapeutic development. The unique structure of salvinorin A has been used to develop longer acting KOPr agonists. OBJECTIVES: We evaluate two novel C-2 analogues of salvinorin A, ethoxymethyl ether Sal B (EOM Sal B) and ß-tetrahydropyran Sal B (ß-THP Sal B) alongside U50,488 for their ability to modulate cocaine-induced behaviours and side effects, pre-clinically. METHODS: Anti-cocaine properties of EOM Sal B were evaluated using the reinstatement model of drug seeking in self-administering rats. EOM Sal B and ß-THP Sal B were evaluated for effects on cocaine-induced hyperactivity, spontaneous locomotor activity and sucrose self-administration. EOM Sal B and ß-THP Sal B were evaluated for aversive, anxiogenic and depressive-like effects using conditioned place aversion (CPA), elevated plus maze (EPM) and forced swim tests (FSTs), respectively. RESULTS: EOM Sal B (0.1, 0.3 mg/kg, intraperitoneally (i.p.)) dose dependently attenuated drug seeking, and EOM Sal B (0.1 mg/kg, i.p.) and ß-THP Sal B (1 mg/kg, i.p.) attenuated cocaine-induced hyperactivity. No effects on locomotor activity, open arm times (EPM) or swimming behaviours (FST) were seen with EOM (0.1 or 0.3 mg/kg, i.p.) or ß-THP Sal B (1 or 2 mg/kg, i.p.). However, ß-THP Sal B decreased time spent in the drug-paired chamber. CONCLUSION: EOM Sal B is more potent than Sal A and ß-THP Sal B in reducing drug-seeking behaviour with fewer side effects. EOM Sal B showed no effects on sucrose self-administration (0.1 mg/kg), locomotor, depressive-like, aversive-like or anxiolytic effects.

Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse.

Acute activation of kappa-opioid receptors produces anti-addictive effects by regulating dopamine levels in the brain. Unfortunately, classic kappa-opioid agonists have undesired side effects such as sedation, aversion, and depression, which restrict their clinical use. Salvinorin A (Sal A), a novel kappa-opioid receptor agonist extracted from the plant Salvia divinorum, has been identified as a potential therapy for drug abuse and addiction. Here, we review the preclinical effects of Sal A in comparison with traditional kappa-opioid agonists and several new analogs. Sal A retains the anti-addictive properties of traditional kappa-opioid receptor agonists with several improvements including reduced side effects. However, the rapid metabolism of Sal A makes it undesirable for clinical development. In an effort to improve the pharmacokinetics and tolerability of this compound, kappa-opioid receptor agonists based on the structure of Sal A have been synthesized. While work in this field is still in progress, several analogs with improved pharmacokinetic profiles have been shown to have anti-addictive effects. While in its infancy, it is clear that these compounds hold promise for the future development of anti-addictive therapeutics.

Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues.

The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the κ-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other κ-opioid agonists.