Serotonin 5-HT1A receptor biased agonists: The challenge of translating an innovative neuropharmacological concept into therapeutics
Résumé
Serotonin 5-HT 1A receptor agonists are prime candidates for CNS drug discovery due to their involvement physiological and pathological processes relevant to neurology and psychiatry. However, the lack of target specificity of many previously characterized agonists has long been a barrier to pharmacological and therapeutic progress. Some of the obstacles may be overcome through the recent concept of biased agonism, which has attracted considerable attention to the development of novel chemical entities at 5-HT, and particularly 5-HT 1A receptors, by specifically targeting intracellular signalling pathways that may themselves be linked to specific brain regions and therapeutic indications. There is now abundant translational data demonstrating distinct molecular and functional pharmacological signatures between different 5-HT 1A receptor agonists, opening new opportunities for research in neurology and psychiatry. Nevertheless, important limitations need to be overcome, including understanding the precise molecular basis for biased agonism, the need for improved translatable models, and the currently limited clinical data on biased agonists. Here, we review the current limits of our knowledge of 5-HT 1A receptor biased agonists and the limitations of available pharmacological tools, counterbalanced by the translational possibilities and therapeutic perspectives opened by novel, highly selective 5-HT1A receptor drug-candidates.
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