Selectivity and Potency of Agonists for the Three Subtypes of Cloned Human β-Adrenoceptors Expressed in Chinese Hamster Ovary Cells

• Published in: The Tohoku Journal of Experimental Medicine Vol. 192; no. 3; pp. 181 - 193
• Main Authors: Yanagisawa, Teruyuki, Sato, Takeya, Yamada, Hiroaki, Sukegawa, Jun, Nunoki, Kazuo
• Format: Journal Article
• Language: English
• Published: Japan Tohoku University Medical Press 01.11.2000
• Subjects: Adrenergic beta-Agonists - pharmacology; Animals; BRL37344; Carboxylic Acids - pharmacology; CHO Cells; cloned human β3-adrenoceptor; Cloning, Molecular; constitutive activity; Cricetinae; Cyclic AMP - metabolism; Dioxins - pharmacology; Dioxoles - pharmacology; Dose-Response Relationship, Drug; Ethanolamines - pharmacology; Humans; isoproterenol; Isoproterenol - pharmacology; Molecular Structure; N-5984; Protein Isoforms - metabolism; Radioligand Assay; Receptors, Adrenergic, beta - chemistry; Receptors, Adrenergic, beta - metabolism; Recombinant Proteins - metabolism
• ISSN: 0040-8727; 1349-3329
• DOI: 10.1620/tjem.192.181

The selectivities, potencies and efficacies of β3-adrenoceptor (β3-AR) agonists on human three β-AR subtypes expressed in Chinese hamster ovary (CHO) cells were investigated using radioligand binding assay and cyclic AMP (cAMP) accumulation assay. The three β-AR subtypes showed the nature of G protein-coupled receptors with the constitutive activity. BRL37344, CL-316, 243 and a newly synthesized β3-AR agonist N-5984, 6-[2-(R)-[[2-(R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-2, 3-dihydro-1, 4-benzodioxine-2-(R)-carboxylic acid, were compared for the potency and selectivity for the β3-AR. In the radioligand binding assay, the affinity of N-5984 for β3-ARs was 14, 70 and 220 times more potent than those of BRL37344, isoproterenol and CL-316, 243, respectively. N-5984 had higher selectivity than BRL37344 for human β3-ARs compared with either for β1-ARs or β2-ARs. N-5984 showed higher potency and intrinsic activity of cAMP production than BRL37344 in CHO cells expressing the β3-ARs. CL-316, 243 had almost no activity of cAMP production in CHO cells expressing any subtype of β-ARs. These results indicate that N-5984 is the most potent and selective agonist for human β3-ARs than any other agonists tested.