Abstract

The β-adrenoceptor activities of trimetoquinol (TMQ) isomers and selected derivatives were evaluated on human β-adrenoceptor subtypes expressed in Chinese hamster ovary cells. In cAMP accumulation assays, (−)-TMQ was 214-, 281-, and 776-fold more potent than (+)-TMQ at stimulating β₁-, β₂-, and β₃-adrenoceptor subtypes, respectively. In radioligand binding assays, (−)-TMQ exhibited 123-, 331-, and 5-fold greater affinity than (+)-TMQ for β₁-, β₂-, and β₃-adrenoceptor subtypes, respectively. (−)-TMQ and (±)-TMQ activated the human β₃-adrenoceptor with an 8.2- and 3.4-fold greater efficacy, respectively, than the reference β-adrenoceptor agonist (−)-isoproterenol (efficacy = 1). The 3′,5′-diiodo analogs of TMQ were partial agonists of the β₂-adrenoceptor relative to (−)-isoproterenol, and their potencies were 5- to 10-fold higher at the β₃-adrenoceptor as compared with β₁-adrenoceptors. Modification of the catechol (6,7-dihydroxy) nucleus, such as replacement of the 7-hydroxy group with a chloro group (7-chloroTMQ), ring fluorination (8-fluoro and 5,8-difluoro analogs), or preparation of bioisosteric tetrahydrothiazolopyridine (THP) derivatives of TMQ yielded compounds that displayed partial agonist activity (relative to (−)-isoproterenol) or were inactive at the β₂-adrenoceptor and exhibited β₃-adrenoceptor-selective stimulation compared with the β₁-adrenoceptor. Furthermore, the 3′,5′-diiodo-4′-methoxybenzylTHP derivative of TMQ was 65-fold more potent than the corresponding 3′,4′,5′-trimethoxybenzylTHP at the human β₃-adrenoceptor. Our results indicate that 6,7-dihydroxy-catechol-modified and 1-benzyl halogen-substituted derivatives of TMQ represent promising leads for the development of β₃-adrenoceptor-selective agonists.