Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton

Hino, Tsubasa; Saitoh, Tohru; Nagumo, Yoko; Yamamoto, Naoshi; Kutsumura, Noriki; Irukayama-Tomobe, Yoko; Ishikawa, Yukiko; Tanimura, Ryuji; Yanagisawa, Masashi; Saitoh, Tsuyoshi

doi:10.1016/j.bmcl.2022.128530

Cited by 7 publications

(5 citation statements)

References 23 publications

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“…4B2) (Hong et al, 2021), probably based on exploration of the chemical space around Nag 26 and YNT-185, in addition to another series (Sabnis, 2020). The chemical space around the original Nagahara hits (Nagahara et al, 2015) has been further explored (Zhang et al, 2021;Hino et al, 2022;Iio et al, 2022;Iio et al, 2023). Most of the reported agonists show some level of OX 2 receptor selectivity, although not as marked as that of Nag 26 and YNT-185 in the original publications (Nagahara et al, 2015;Irukayama-Tomobe et al, 2017); however, a lower OX 2 vs. OX 1 -selectivity for Nag 26 than originally reported has also been demonstrated (Rinne et al, 2018).…”

Section: Small Molecule Orexin Receptor Agonistsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology

Kukkonen,

Jacobson,

Hoyer

et al. 2024

Pharmacol Rev

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Section: Small Molecule Orexin Receptor Agonistsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology

Kukkonen,

Jacobson,

Hoyer

et al. 2024

Pharmacol Rev

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“…These are very recent studies, which open the possibility of a clearer understanding of pharmacophores orientation in the space for optimal interaction with the OX2-R in its active state. 107 As a continuation of the naphtalene series, in 2022, Iio et al probed the chirality of 1-amino-tetraline skeleton, obtaining the series through reduction of the naphtalene ring of 58, which was also derived by the rigid putative conformation of YNT-185 (Figure 28). 108 The introduction of the N-methyl-(3-methoxyphenyl)acetamide group on aliphatic chains or alicyclic groups was detrimental.…”

Section: Naphthalenes and Tetralinesmentioning

confidence: 99%

“…They also highlighted the importance of the benzamide rotamer in the trans isomer conformation. These are very recent studies, which open the possibility of a clearer understanding of pharmacophores orientation in the space for optimal interaction with the OX2‐R in its active state 107 …”

Section: Newly Developed Ox‐r Ligandsmentioning

confidence: 99%

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

Bonifazi

Bello

Giorgioni

et al. 2023

Medicinal Research Reviews

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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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“…Recently, a dual orexin receptor agonist, RTOXA-43, in which the dimethylcarbamoyl group of YNT-185 was replaced with a 4-pyridylmethylcarbamoyl group, has been disclosed to exhibit comparable agonist activity for both OX 1 R and OX 2 R (EC 50 = 24 nM for both receptors) . Moreover, we have independently reported ( R )- 2 , which is derived from a naphthalene-type OX 2 R agonist and exhibits highly potent agonist activity for both receptors (EC 50 = 13.5 nM for OX 1 R, 0.579 nM for OX 2 R). , Recently, the active-state cryogenic electron microscopy (cryo-EM) structures of OX 2 R bound with YNT-185 derivative 1 and TAK-925 have been reported. , Despite the significant progress in the development of OX 2 R-selective and dual OX 1/2 R agonists, no OX 1 R-selective agonists have been reported so far.…”

Section: Introductionmentioning

confidence: 99%

“…31 ently reported (R)-2, which is derived from a naphthalene-type OX 2 R agonist and exhibits highly potent agonist activity for both receptors (EC 50 = 13.5 nM for OX 1 R, 0.579 nM for OX 2 R). 32,33 Recently, the active-state cryogenic electron microscopy (cryo-EM) structures of OX 2 R bound with YNT-185 derivative 1 and TAK-925 have been reported. 28,34 Despite the significant progress in the development of OX 2 R-selective and dual OX 1/2 R agonists, no OX 1 R-selective agonists have been reported so far.…”

Section: ■ Introductionmentioning

confidence: 99%

Design and Synthesis of Orexin 1 Receptor-Selective Agonists

et al. 2023

Self Cite

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Orexins are a family of neuropeptides that regulate various physiological events, such as sleep/wakefulness as well as emotional and feeding behavior, and that act on two G-protein-coupled receptors, i.e., orexin 1 (OX1R) and orexin 2 receptors (OX2R). Since the discovery that dysfunction of the orexin/OX2R system causes the sleep disorder narcolepsy, several OX2R-selective and OX1/2R dual agonists have been disclosed. However, an OX1R-selective agonist has not yet been reported, despite the importance of the biological function of OX1R. Herein, we report the discovery of a potent OX1R-selective agonist, (R,E)-3-(4-methoxy-3-(N-(8-(2-(3-methoxyphenyl)-N-methylacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)phenyl)-N-(pyridin-4-yl)acrylamide [(R)-YNT-3708; EC50 = 7.48 nM for OX1R; OX2R/OX1R EC50 ratio = 22.5]. The OX1R-selective agonist (R)-YNT-3708 exhibited antinociceptive and reinforcing effects through the activation of OX1R in mice.

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Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton

Cited by 7 publications

References 23 publications

International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology

International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology

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

Design and Synthesis of Orexin 1 Receptor-Selective Agonists

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