TY - JOUR
T1 - Targeting orexin receptors
T2 - Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders
AU - Bonifazi, Alessandro
AU - Del Bello, Fabio
AU - Giorgioni, Gianfabio
AU - Piergentili, Alessandro
AU - Saab, Elizabeth
AU - Botticelli, Luca
AU - Cifani, Carlo
AU - Micioni Di Bonaventura, Emanuela
AU - Micioni Di Bonaventura, Maria Vittoria
AU - Quaglia, Wilma
N1 - Publisher Copyright:
© 2023 Wiley Periodicals LLC.
PY - 2023/9
Y1 - 2023/9
N2 - 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.
AB - 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.
KW - dual OX-R ligands
KW - neuropsychiatric disorders
KW - orexin receptors
KW - poly-pharmacology
KW - selective agonists or antagonists
UR - http://www.scopus.com/inward/record.url?scp=85152264471&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85152264471&partnerID=8YFLogxK
U2 - 10.1002/med.21959
DO - 10.1002/med.21959
M3 - Review article
C2 - 37036052
AN - SCOPUS:85152264471
SN - 0198-6325
VL - 43
SP - 1607
EP - 1667
JO - Medicinal Research Reviews
JF - Medicinal Research Reviews
IS - 5
ER -