Synthesis and human beta-adrenoceptor activity of 1-(3,5-diiodo-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol derivatives in vitro

Trimetoquinol (I, TMQ) is a potent nonselective beta-adrenergic receptor (A R) 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 treatmen t 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 correspond ing amides followed by NaBH4 reduction, and the halogens in the aromatic ri ng A were introduced by direct halogenation of protected compound 11. Where as halogen substitution in ring A reduced either potency or intrinsic activ ity on beta(3)-AR, the non-halogen-substituted compounds 8 and 10 were pote nt, selective, nearly full agonists for beta(3)-AR.