title: Synthesis and human beta-adrenoceptor activity of 1-(3,5-diiodo-4- methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol derivatives in vitro.
abstract: Trimetoquinol (1, TMQ) is a potent nonselective beta-adrenergic receptor (AR) agonist and a thromboxane A(2)/prostaglandin endoperoxide (TP) receptor antagonist, while 3',5'-diiodo-TMQ (2) exhibits beta(3)-AR selectivity. In search of selective beta(3)-AR agonists as potential drugs for the treatment of human obesity and type II diabetes mellitus, a series of 1-(3, 5-diiodo-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ols has been prepared and evaluated for their biological activities at human beta(1)-, beta(2)-, and beta(3)-ARs expressed in Chinese hamster ovary (CHO) cells. The compounds have been synthesized by the Bischler-Napieralski cyclization of corresponding amides followed by NaBH(4) reduction, and the halogens in the aromatic ring A were introduced by direct halogenation of protected compound 11. Whereas halogen substitution in ring A reduced either potency or intrinsic activity on beta(3)-AR, the non-halogen-substituted compounds 8 and 10 were potent, selective, nearly full agonists for beta(3)-AR.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee-Memphis, Memphis, Tennessee 38163, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.forename: V I
authors.initials: VI
authors.lastname: Nikulin
authors.forename: S S
authors.initials: SS
authors.lastname: Vansal
authors.forename: D R
authors.initials: DR
authors.lastname: Feller
authors.forename: D D
authors.initials: DD
authors.lastname: Miller
mesh_terms: D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011863:Radioimmunoassay; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D000318:Adrenergic beta-Agonists; D007546:Isoquinolines; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP