Salvindolin elicits opioid system-mediated antinociceptive and antidepressant-like activities

Abstract

Background: Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects. Aims: In this article, we present its new semisynthetic analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities. Methods: Competitive binding studies were performed for salvindolin with kappa opioid and mu opioid. The mouse model of nociception (acetic-acid-induced writhing, formalin, and hot plate tests), depression (forced swim and tail suspension tests), and the open field test, were used to evaluate antinociceptive, antidepressant-like, and locomotion effects, respectively, of salvindolin. We built a 3-D molecular model of the kappa opioid receptor, using a mu opioid X-ray crystal structure as a template, and docked salvindolin into the two proteins. Results/outcomes: Salvindolin showed affinity towards kappa opioid and mu opioid receptors but with 100-fold mu opioid preference. Tests of salvindolin in mice revealed good oral bioavailability, antinociceptive, and antidepressive-like effects, without locomotor incoordination. Docking of salvindolin showed strong interactions with the mu opioid receptor which matched well with experimental binding data. Salvindolin-induced behavioral changes in the hot plate and forced swim tests were attenuated by naloxone (nonselective opioid receptor antagonist) and/or naloxonazine (selective mu opioid receptor antagonist) but not by nor-binaltorphimine (selective kappa opioid receptor antagonist). In addition, WAY100635 (a selective serotonin 1A receptor antagonist) blocked the antidepressant-like effect of salvindolin. Conclusions/interpretation: By simple chemical modification, we were able to modulate the pharmacological profile of salvinorin A, a highly selective kappa opioid receptor agonist, to salvindolin, a ligand with preferential mu opioid receptor affinity and activity on the serotonin 1A receptor. With its significant antinociceptive and antidepressive-like activities, salvindolin has the potential to be an analgesic and/or antidepressant drug candidate.

Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects

“…This new molecule showed antinociceptive effects mediated by MOP and KOP receptors, and antidepressant-like properties mediated by MOP/5-HT 1A receptor activation, without the psychotropic side effects usually associated with salvinorin A. Another aromatic analogue of salvinorin A obtained through the integration of a benzoyl moiety at the C2-position, herkinorin, was previously reported as the first non-nitrogenous compound with greater affinity for the MOP receptor over the KOP receptor [78,204]. This compound, unlike other MOP agonists, did not induce MOP signalling through the β-arrestin-2 pathway nor promote receptor internalisation.…”

“…When S. divinorum leaves are masticated, the juice must be retained in the mouth for approximately 10 min, before being spat out or swallowed, to enable the absorption through the oral mucosa of enough salvinorin A to produce psychoactive effects [2,15]. The percentage of salvinorin A being absorbed through the oral route in humans was reported to be around 85.8% [78]. Through sublingual administration of salvinorin A in a DMSO/PEG-400 vehicle, doses up to 4 mg exerted no psychoactive effects in eight volunteers [79], suggesting low bioavailability of salvinorin A through this absorption route.…”

“…Another synthetic derivative, salvinorin B methoxymethyl ether, proved to be more potent than salvinorin A, inducing antinociception effects, and having antiaddiction properties towards cocaine consumption with a longer-lasting action [202,203]. The development of a salvinorin A aromatic analogue, salvindolin, was recently proposed for therapeutic purposes through modification of the C2-side chain with a 2-indolyl moiety [78]. This new molecule showed antinociceptive effects mediated by MOP and KOP receptors, and antidepressant-like properties mediated by MOP/5-HT 1A receptor activation, without the psychotropic side effects usually associated with salvinorin A.…”

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant

“…Recently, Keasling and colleagues evaluated the effects of salvinolin, a new semisynthetic analog of salvinorin A, with mu opioid receptor affinity. In summary, salvinolin demonstrated good oral bioavailability and showed antidepressant-like effect that was blocked by the selective 5HT 1A antagonist WAY100635 [332]. Another derivative of salvinorin A, the 22-azido salvinorin A, also promoted an antidepressant-like effect linked to its ability of inhibiting monoamine oxidase (MAO) enzyme, as well as to its affinity for α1A, α1B, α1D adrenergic receptors beyond KOR [333].…”

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-based Antagonists and Kappa Opioid Receptor

“…28 Additionally, salvinorin A has been used as an important prototype for the development of related drug candidates. [29][30][31][32][33][34][35][36][37][38][39] Notably, there are only six salvinorin-based compounds in the literature that have demonstrated antagonism against any of the opioid receptors (1-6, Figure 2); 39 all other reported salvinorin-based compounds are agonists. Compounds 1-5 are antagonists at KOR, μ-opioid receptor (MOR), and δ-opioid receptor (DOR), with 1 being the most selective for KOR.…”