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

Abstract

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 β-tetrahydropyran Sal B (β-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 β-THP Sal B were evaluated for effects on cocaine-induced hyperactivity, spontaneous locomotor activity and sucrose self-administration. EOM Sal B and β-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 (FST) respectively. Results EOM Sal B (0.1, 0.3 mg/kg, i.p.) dose-dependently attenuated drug-seeking and EOM Sal B (0.1 mg/kg, i.p.) and β-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 β-THP Sal B (1 or 2 mg/kg, i.p.). However, β-THP Sal B decreased time spent in the drug-paired chamber. Conclusion EOM Sal B is more potent than Sal A and β-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.

Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents

“…While we confirm the aversive properties of U50488 (10 mg/kg) ( Figure 8 a) seen in previous studies [ 104 ], Mesyl Sal B (0.3 mg/kg) had no effects on either place aversion ( Figure 8 b) or taste aversion ( Figure 8 c). Similar results were found for another more potent Sal A analogue, 2-ethoxymethyl ether Sal B (0.1 mg/kg), which did not show aversive effects in the CPA paradigm [ 34 ]. This further supports the proposition that it is possible to modulate drug-seeking at doses that do not have aversive effects, with both Sal A and Mesyl Sal B showing no significant aversive effects.…”

“…Previous findings show that Sal A (0.25–2 mg/kg) induces depressive effects without suppressing locomotion activity in rats [ 30 , 72 ]. Similarly, another Sal A analogue, MOM Sal B (0.3 mg/kg) showed pro-depressive effects [ 47 ], whereas 2-ethoxymethyl ether Sal B (0.3 mg/kg) and β-tetrahydropyran Sal B (2 mg/kg) did not [ 34 ]. Since a reduction in swimming time is related to the modulation in serotonin transporter function [ 108 ], depressive effects produced by these novel neoclerodanes may also involve alterations in central serotonin systems.…”

“…Sal A has a novel neo-clerodane diterpene structure and shares similar pharmacological properties with the traditional KOPr agonists [ 30 , 31 , 32 ]. Previously, we have reported that Sal A and the analogues, 2-ethoxymethyl ether Sal B and β-tetrahydropyran Sal B, attenuate cocaine-prime induced cocaine seeking without inducing sedation or suppressing operant sucrose reinforcement in rats in a similar fashion to the traditional KOPr agonists U50488, U69593, and spiradoline [ 33 , 34 ]. However, Sal A has a rapid onset and short duration of the effects [ 35 , 36 , 37 ] attributed to the quick metabolism at the C-2 position to the metabolite Salvinorin B [ 29 , 35 ].…”

“…Recently, C-2 substituted Sal A analogues have been synthesized with varying affinity for KOPr compared to Sal A [ 41 , 43 ]. Other pharmacological studies indicate that C-2 substituted Sal A analogues are longer acting [ 32 , 34 , 44 ]. Therefore, developing Sal A analogues with anti-cocaine properties, improved pharmacokinetics, and fewer side-effects are desirable for the development of potential anti-cocaine pharmacotherapies [ 32 , 45 , 46 , 47 , 48 ].…”

A single, extinction-based treatment with a kappa opioid receptor agonist elicits a long-term reduction in cocaine relapse

“…By contrast, KOR agonists reduce both cocaine taking and cocaine-primed reinstatement acutely, during KOR agonist exposure [ 4 , 5 , 24 – 26 ]. Thus, KOR agonists may be particularly therapeutic when combined with cocaine, perhaps through their known ability to oppose cocaine reward [ 8 ].…”