title: N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist.
abstract: The identification of potent and selective orexin-2 receptor (OX(2)R) antagonists is described based on the modification of N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogue 1, recently discovered during high throughput screening (HTS). Substitution of an acyl group in 1 with tert-Leucine (tert-Leu), and introduction of a 4-pyridylmethyl substituent onto the amino function of tert-Leu improved compound potency, selectivity, and water solubility. Thus, compound 29 is a promising tool to investigate the role of orexin-2 receptors.
authors.affiliation: Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba 300-2611, Ibaraki, Japan. hirosems@banyu.co.jp
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hirose
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Egashira
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Goto
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashihayata
authors.forename: Norikazu
authors.initials: N
authors.lastname: Ohtake
authors.forename: Hisashi
authors.initials: H
authors.lastname: Iwaasa
authors.forename: Mikiko
authors.initials: M
authors.lastname: Hata
authors.forename: Takehiro
authors.initials: T
authors.lastname: Fukami
authors.forename: Akio
authors.initials: A
authors.lastname: Kanatani
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
mesh_terms: D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D044005:Tetrahydroisoquinolines