Serotonin-releasing agents with reduced off-target effects

Autor: Felix P Mayer, Marco Niello, Daniela Cintulova, Spyridon Sideromenos, Julian Maier, Yang Li, Simon Bulling, Oliver Kudlacek, Klaus Schicker, Hideki Iwamoto, Fei Deng, Jinxia Wang, Marion Holy, Rani Katamish, Walter Sandtner, Yulong Li, Daniela Pollak, Randy D Blakely, Marko Mihovilovic, Michael H Baumann, Harald H Sitte
Rok vydání: 2022
Předmět:
Zdroj: Molecular Psychiatry. 28:722-732
ISSN: 1476-5578
1359-4184
DOI: 10.1038/s41380-022-01843-w
Popis: 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.
Databáze: OpenAIRE
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