Novel and potent human and rat beta3-adrenergic receptor agonists containing substituted 3-indolylalkylamines.
A novel series of 2-(3-indolyl)alkylamino-1-(3-chlorophenyl)ethanols was prepared and evaluated for in vitro ability to stimulate cAMP production in Chinese hamster ovary cells expressing cloned human beta(3)-AR. The optically active 30a was found to be the most potent and selective human beta(3)-AR agonist in this series with an EC(50) value of 0.062nM. In addition, 30a selectivity for human beta(3)-AR was 210-fold and 103-fold that for human beta(2)-AR and beta(1)-AR, respectively. Furthermore, 30a showed potent agonistic activity at rat beta(3)-AR.
Harada
Hiroshi
H
Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Enoki, Suita, Japan. hiroshi-harada@dainippon-pharm.co.jp
Hirokawa
Yoshimi
Y
Suzuki
Kenji
K
Hiyama
Yoichi
Y
Oue
Mayumi
M
Kawashima
Hitoshi
H
Yoshida
Naoyuki
N
Furutani
Yasuji
Y
Kato
Shiro
S
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000473:Alkanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000138:chemical synthesis / Q000494:pharmacology
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000473:Alkanes; D004983:Ethanolamines; D007211:Indoles; D014363:Tryptamines; C057368:BRL 37344; D000242:Cyclic AMP