Serotonin 5-HT1A receptor biased agonists: The challenge of translating an innovative neuropharmacological concept into therapeutics

Serotonin 5-HT1A 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-HT1A 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-HT1A 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-HT1A 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. This article is part of the Special Issue on "Ligand Bias". •Serotonin 5-HT1A receptor agonists are prime candidates for CNS drug discovery.•The lack of specificity of classical agonists has long been a barrier to pharmacological progress.•The recent concept of 5-HT1A biased agonism implies targeting specific brain regions for different therapeutic indications.•The current limitations of knowledge on biased agonism are balanced by their translational potential and therapeutic promise.