Selectivity and potency of agonists for the three subtypes of cloned human beta-adrenoceptors expressed in Chinese hamster ovary cells.
The selectivities, potencies and efficacies of beta3-adrenoceptor (beta3-AR) agonists on human three beta-AR subtypes expressed in Chinese hamster ovary (CHO) cells were investigated using radioligand binding assay and cyclic AMP (cAMP) accumulation assay. The three beta-AR subtypes showed the nature of G protein-coupled receptors with the constitutive activity. BRL37344, CL-316,243 and a newly synthesized beta3-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 beta3-AR. In the radioligand binding assay, the affinity of N-5984 for beta3-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 beta3-ARs compared with either for beta1-ARs or beta2-ARs. N-5984 showed higher potency and intrinsic activity of cAMP production than BRL37344 in CHO cells expressing the beta3-ARs. CL-316,243 had almost no activity of cAMP production in CHO cells expressing any subtype of beta-ARs. These results indicate that N-5984 is the most potent and selective agonist for human beta3-ARs than any other agonists tested.
Department of Physiology, Tohoku University School of Medicine, Sendai, Japan. yanagswt@mail.cc.tohoku.ac.jp
T
T
Yanagisawa
T
T
Sato
H
H
Yamada
J
J
Sukegawa
K
K
Nunoki
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002264:Carboxylic Acids / Q000494:pharmacology*; D003001:Cloning, Molecular; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004147:Dioxins / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D015394:Molecular Structure; D020033:Protein Isoforms / Q000378:metabolism; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
C431889:6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxine-2-(R)-carboxylic acid; D000318:Adrenergic beta-Agonists; D002264:Carboxylic Acids; D004147:Dioxins; D004149:Dioxoles; D004983:Ethanolamines; D020033:Protein Isoforms; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; C057368:BRL 37344; D000242:Cyclic AMP; D007545:Isoproterenol