Salvinorin A, a compound from the leaves of Salvia divinorum, activates κ-opioid receptors and could be a basis for treating substance abuse. Researchers synthesized several derivatives with modified furan rings to better understand how this part of the molecule binds to the receptor. Functional assays showed that smaller substitutions are preferred, indicating the furan ring fits into a tight part of the binding pocket. The most potent analogue reduced drug-seeking behavior in an animal model of relapse without causing sedation, a common side effect of other κ-opioid agonists.
Ibogaine, the main psychoactive alkaloid in Tabernanthe iboga, has been studied for decades as a possible treatment for substance use disorders because it may interrupt addiction to multiple drugs. Its inhibition of α3β4 nicotinic acetylcholine receptors in the brain is a likely mechanism for this anti-addictive effect. This perspective examines several classes of compounds developed to target α3β4 nAChRs, focusing on those effective in pre-clinical models of drug abuse and evaluated clinically. It highlights the promising potential of α3β4 nAChRs as viable targets for treating a wide array of substance use disorders and discusses challenges that must be overcome to develop these ligands into therapeutic treatments.