Serotonin-releasing agents with reduced off-target effects

Abstract Increasing extracellular levels of serotonin (5-HT) in the brain ameliorates symptoms of depression and anxiety-related disorders, e.g. social phobias and post-traumatic stress disorder. Recent evidence from preclinical and clinical studies established the potential of drugs inducing the release of 5-HT via the 5-HT-transporter. Nevertheless, current 5-HT releasing compounds under clinical investigation carry the risk for abuse and deleterious side effects. Here, we demonstrate that S-enantiomers of certain ring-substituted cathinones show preference for the release of 5-HT ex vivo and in vivo, and exert 5-HT-associated effects in preclinical behavioral models. Importantly, the lead cathinone compounds (i) do not induce substantial dopamine release and (ii) display reduced off-target activity at vesicular monoamine transporter-2 and 5-HT2B-receptors; indicative of low abuse-liability and low potential for adverse events. Taken together, our findings identify these agents as first-in class leads that may prove useful for the treatment of disorders where elevation of 5-HT has proven beneficial.