beta-adrenoceptor subtype activities of trimetoquinol derivatives: Biochemical studies on human beta-adrenoceptors expressed in Chinese hamster ovarycells

The beta-adrenoceptor activities of trimetoquinol (TMQ) isomers and selecte d derivatives were evaluated on human beta-adrenoceptor subtypes expressed in Chinese hamster ovary cells. In cAMP accumulation assays, (-)- TMQ was 2 14-, 281-, and 776-fold more potent than (+)- TMQ at stimulating beta(1)-, beta(2)-, and beta(3)-adrenoceptor subtypes, respectively. In radioligand b inding assays, (-)- TMQ exhibited 123-, 331-, and 5-fold greater affinity t han (1)- TMQ for beta(1)-, beta(2)-, and beta(3)-adrenoceptor subtypes, res pectively. (-)- TMQ and (+/-)- TMQ activated the human beta(3)-adrenoceptor with an 8.2- and 3.4- fold greater efficacy, respectively, than the refere nce beta-adrenoceptor agonist (-)- isoproterenol (efficacy = 1). The 3',5'- diiodo analogs of TMQ were partial agonists of the beta(2)-adrenoceptor rel ative to (-)- isoproterenol, and their potencies were 5- to 10-fold higher at the beta(3)-adrenoceptor as compared with beta(1)-adrenoceptors. Modific ation of the catechol (6,7-dihydroxy) nucleus, such as replacement of the 7 -hydroxy group with a chloro group (7-chloroTMQ), ring fluorination (8-fluo ro and 5,8-difluoro analogs), or preparation of bioisosteric tetrahydrothia zolopyridine (THP) derivatives of TMQ yielded compounds that displayed part ial agonist activity (relative to (-)- isoproterenol) or were inactive at t he beta(2)-adrenoceptor and exhibited beta(3)-adrenoceptor-selective stimul ation compared with the beta(1)-adrenoceptor. Furthermore, the 3',5'-diiodo -4'-methoxybenzylTHP derivative of TMQ was 65-fold more potent than the cor responding 3',4',5'-trimethoxybenzylTHP at the human beta(3)-adrenoceptor. Our results indicate that 6,7-dihydroxy-catechol-modified and 1-benzyl halo gen-substituted derivatives of TMQ represent promising leads for the develo pment of beta(3)-adrenoceptor-selective agonists.