Discovery of orexin 2 receptor selective and dual orexin receptor agonists based on the tetralin structure: Switching of receptor selectivity by chirality on the tetralin ring

Iio, Keita; Ohshita, Ryuichiro; Hino, Tsubasa; Amezawa, Mao; Takayama, Yoshiaki; Nagumo, Yoko; Yamamoto, Naoshi; Kutsumura, Noriki; Irukayama-Tomobe, Yoko; Ishikawa, Yukiko; Tanimura, Ryuji; Yanagisawa, Masashi; Saitoh, Tsuyoshi

doi:10.1016/j.bmcl.2022.128555

Cited by 8 publications

(17 citation statements)

References 28 publications

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“…In our previous study, separation of the enantiomers of tetralin derivative (rac)-2 identified the (R)-tetralin core structure as a eutomer structure for both receptors. 33 While we also separated the optical isomers of (rac)-18 using preparative chiral HPLC, the individual isomers did not crystallize, whereas (rac)-18 crystallized. Therefore, the absolute stereochemistry of each isomer was determined by asymmetric synthesis of the (R)-isomer from optically pure (R)-21 33 according to the same procedure as (rac)-18 (Scheme 1) and comparison of the optical properties.…”

Section: Synthetic Chemistry and Eutomer Determinationmentioning

confidence: 91%

“…33 While we also separated the optical isomers of (rac)-18 using preparative chiral HPLC, the individual isomers did not crystallize, whereas (rac)-18 crystallized. Therefore, the absolute stereochemistry of each isomer was determined by asymmetric synthesis of the (R)-isomer from optically pure (R)-21 33 according to the same procedure as (rac)-18 (Scheme 1) and comparison of the optical properties. Consistent with our previous research, (R)-…”

Section: Synthetic Chemistry and Eutomer Determinationmentioning

confidence: 91%

“…The common intermediate 21 was prepared according to a previously reported method. 33 Initially, 21 was treated with 5-bromo-2methoxybenzenesulfonyl chloride to yield intermediate 22. Suzuki-Miyaura coupling with phenylboronic acid and hydrogenation of 22 furnished 3 and 4, respectively.…”

Section: Synthetic Chemistry and Eutomer Determinationmentioning

confidence: 99%

“…31 Moreover, we have independently reported (R)-2, which is derived from a naphthalene-type OX2R agonist and exhibits highly potent agonist activity for both receptors (EC50 = 13.5 nM for OX1R, 0.579 nM for OX2R). 32,33 Despite the significant progress in the development of OX2R-selective and dual OX1/2R agonists, no OX1R-selective agonists have been reported so far. ).…”

Section: Introductionmentioning

confidence: 99%

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Design and synthesis of orexin 1 receptor-selective agonists

Iio

Hashimoto

Nagumo

et al. 2022

Preprint

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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., the 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). Unlike the OX2R-selective agonist, the OX1R-selective agonist (R)-YNT-3708 exhibited antinociceptive and reinforcing effects in mice more potently than the dual agonist.

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Section: Synthetic Chemistry and Eutomer Determinationmentioning

confidence: 91%

Section: Synthetic Chemistry and Eutomer Determinationmentioning

confidence: 91%

Section: Synthetic Chemistry and Eutomer Determinationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Design and synthesis of orexin 1 receptor-selective agonists

Iio

Hashimoto

Nagumo

et al. 2022

Preprint

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show abstract

“…In our previous study, the separation of the enantiomers of the tetralin derivative (rac)-2 identified the (R)-tetralin core structure as a eutomer structure for both receptors. 33 While we also separated the optical isomers of (rac)-18 using preparative chiral HPLC, the individual isomers did not crystallize, whereas (rac)-18 crystallized. Therefore, the absolute stereochemistry of each isomer was determined by asymmetric synthesis of the (R)-isomer from optically pure (R)-21 33 according to the same procedure as (rac)-18 (Scheme 1) and comparison of the optical properties.…”

Section: Determinationmentioning

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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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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Discovery of orexin 2 receptor selective and dual orexin receptor agonists based on the tetralin structure: Switching of receptor selectivity by chirality on the tetralin ring

Cited by 8 publications

References 28 publications

Design and synthesis of orexin 1 receptor-selective agonists

Design and synthesis of orexin 1 receptor-selective agonists

Design and Synthesis of Orexin 1 Receptor-Selective Agonists

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

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