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- Title
Salvindolin elicits opioid system-mediated antinociceptive and antidepressant-like activities.
- Authors
Keasling, Adam W; Pandey, Pankaj; Doerksen, Robert J; Pedrino, Gustavo R; Costa, Elson A; da Cunha, Luiz C; Zjawiony, Jordan K; Fajemiroye, James O
- Abstract
<bold>Background: </bold>Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects.<bold>Aims: </bold>In this article, we present its new semisynthetic analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities.<bold>Methods: </bold>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.<bold>Results/outcomes: </bold>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.<bold>Conclusions/interpretation: </bold>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.
- Subjects
ANTIDEPRESSANTS; SALVINORIN A; OPIOID receptors; SEROTONIN receptors; BEHAVIOR; MOLECULAR models; MOLECULAR docking
- Publication
Journal of Psychopharmacology, 2019, Vol 33, Issue 7, p865
- ISSN
0269-8811
- Publication type
journal article
- DOI
10.1177/0269881119849821