Targeting orexin receptors: Recent advances inthe development of subtype selective or dualligands for the treatment of neuropsychiatricdisorders

NIDA-IRP authors Lily Saab, B.S. and Alessandro Bonifazi, Pharm.D./Ph.D.

Reviews To Read – April 2023.

Published in Medical Research Reviews with contributions from Alessandro Bonifazi and Lily Saab of the NIDA IRP Medicinal Chemistry Section.

This review, written in collaboration between authors from the Medicinal Chemistry Section (NIDA-IRP) and the Medicinal Chemistry and Pharmacology Units at the University of Camerino (Italy), is focused on the development of small molecules acting as agonists or antagonists for the orexin receptor subtypes OX1-R and OX2-R. Given the wide expression of OX‐Rs in different central nervous system and peripheral areas, the pharmacological effects and potential therapeutic applications of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed, alongside a perspective point of view on poly-pharmacology and multi-target approaches.

Alessandro Bonifazi; Fabio Del Bello; Gianfabio Giorgioni; Alessandro Piergentili; Elizabeth Saab; Luca Botticelli; Carlo Cifani; Emanuela Micioni Di Bonaventura; Maria Vittoria Micioni Di Bonaventura; Wilma Quaglia

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders Journal Article

In: Med Res Rev, 2023, ISSN: 1098-1128.

Abstract | Links

@article{pmid37036052b,

title = {Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders},

author = {Alessandro Bonifazi and Fabio Del Bello and Gianfabio Giorgioni and Alessandro Piergentili and Elizabeth Saab and Luca Botticelli and Carlo Cifani and Emanuela Micioni Di Bonaventura and Maria Vittoria Micioni Di Bonaventura and Wilma Quaglia},

url = {https://pubmed.ncbi.nlm.nih.gov/37036052/},

doi = {10.1002/med.21959},

issn = {1098-1128},

year  = {2023},

date = {2023-04-01},

urldate = {2023-04-01},

journal = {Med Res Rev},

abstract = {Orexin-A and orexin-B, also named hypocretin-1 and hypocretin-2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein-coupled receptors, namely orexin receptor type 1 (OX1-R) and type 2 (OX2-R), which share 64% amino acid identity. Given the wide expression of OX-Rs in different central nervous system and peripheral areas and the several pathophysiological functions in which they are involved, including sleep-wake cycle regulation (mainly mediated by OX2-R), emotion, panic-like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1-R), both subtypes represent targets of interest for many structure-activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual-orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1-R and OX2-R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype-selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1-R/OX2-R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX-R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly-pharmacology applications and multitarget ligands have also been considered.},

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pubstate = {published},

tppubtype = {article}

}