TY - JOUR
T1 - Advances in drug design and therapeutic potential of selective or multitarget 5-HT1A receptor ligands
AU - Giorgioni, Gianfabio
AU - Bonifazi, Alessandro
AU - Botticelli, Luca
AU - Cifani, Carlo
AU - Matteucci, Federica
AU - Micioni Di Bonaventura, Emanuela
AU - Micioni Di Bonaventura, Maria Vittoria
AU - Giannella, Mario
AU - Piergentili, Alessandro
AU - Piergentili, Alessia
AU - Quaglia, Wilma
AU - Del Bello, Fabio
N1 - Publisher Copyright:
© 2024 Wiley Periodicals LLC.
PY - 2024/11
Y1 - 2024/11
N2 - 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.
AB - 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.
KW - biased 5-HT1A-R agonists
KW - imaging tools
KW - multitarget ligands
KW - neuropsychiatric disorders
KW - serotonin 5-HT1A receptor
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U2 - 10.1002/med.22049
DO - 10.1002/med.22049
M3 - Review article
AN - SCOPUS:85194746365
SN - 0198-6325
VL - 44
SP - 2640
EP - 2706
JO - Medicinal Research Reviews
JF - Medicinal Research Reviews
IS - 6
ER -