Advances in drug design and therapeutic potential of selective or multitarget 5‐HT1A receptor ligands

Abstract 5‐HT1A receptor (5‐HT1A‐R) is a serotoninergic G‐protein coupled receptor subtype which contributes to several physiological processes in both central nervous system and periphery. Despite being the first 5‐HT‐R identified, cloned and studied, it still represents a very attractive target in drug discovery and continues to be the focus of a myriad of drug discovery campaigns due to its involvement in numerous neuropsychiatric disorders. The structure‐activity relationship studies (SAR) performed over the last years have been devoted to three main goals: (i) design and synthesis of 5‐HT1A‐R selective/preferential ligands; (ii) identification of 5‐HT1A‐R biased agonists, differentiating pre‐ versus post‐synaptic agonism and signaling cellular mechanisms; (iii) development of multitarget compounds endowed with well‐defined poly‐pharmacological profiles targeting 5‐HT1A‐R along with other serotonin receptors, serotonin transporter (SERT), D2‐like receptors and/or enzymes, such as acetylcholinesterase and phosphodiesterase, as a promising strategy for the management of complex psychiatric and neurodegenerative disorders. In this review, medicinal chemistry aspects of ligands acting as selective/preferential or multitarget 5‐HT1A‐R agonists and antagonists belonging to different chemotypes and developed in the last 7 years (2017–2023) have been discussed. The development of chemical and pharmacological 5‐HT1A‐R tools for molecular imaging have also been described. Finally, the pharmacological interest of 5‐HT1A‐R and the therapeutic potential of ligands targeting this receptor have been considered.