N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist.
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.
Hirose
Masaaki
M
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba 300-2611, Ibaraki, Japan. hirosems@banyu.co.jp
Egashira
Shin-ichiro
S
Goto
Yasuhiro
Y
Hashihayata
Takashi
T
Ohtake
Norikazu
N
Iwaasa
Hisashi
H
Hata
Mikiko
M
Fukami
Takehiro
T
Kanatani
Akio
A
Yamada
Koji
K
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*
D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D044005:Tetrahydroisoquinolines