Vol. 291, Issue 2, 875-883, November 1999

-Adrenoceptor Subtype Activities of Trimetoquinol Derivatives: Biochemical Studies on Human -Adrenoceptors Expressed in Chinese Hamster Ovary Cells¹

Anish A. Konkar, Sandeep S. Vansal, Gamal Shams, Paul F. Fraundorfer, Wei-Ping Zheng, Victor I. Nikulin, Joseph De Los Angeles, Richard H. Fertel, Duane D. Miller and Dennis R. Feller

Division of Pharmacology (A.A.K., G.S., P.F.F., D.R.F.), College of Pharmacy and Department of Pharmacology (R.H.F.), College of Medicine, The Ohio State University, Columbus, Ohio; Department of Pharmaceutical Sciences (W.-P.Z, V.I.N., J.D.L.A., D.D.M.), College of Pharmacy, University of Tennessee at Memphis, Memphis, Tennessee; and Department of Pharmacology (S.S.V., D.R.F.) and National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, Mississippi

The -adrenoceptor activities of trimetoquinol (TMQ) isomers and selected derivatives were evaluated on human -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 ₁-, ₂-, and ₃-adrenoceptor subtypes, respectively. In radioligand binding assays, ()-TMQ exhibited 123-, 331-, and 5-fold greater affinity than (+)-TMQ for ₁-, ₂-, and ₃-adrenoceptor subtypes, respectively. ()-TMQ and (±)-TMQ activated the human ₃-adrenoceptor with an 8.2- and 3.4-fold greater efficacy, respectively, than the reference -adrenoceptor agonist ()-isoproterenol (efficacy = 1). The 3',5'-diiodo analogs of TMQ were partial agonists of the ₂-adrenoceptor relative to ()-isoproterenol, and their potencies were 5- to 10-fold higher at the ₃-adrenoceptor as compared with ₁-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 ₂-adrenoceptor and exhibited ₃-adrenoceptor-selective stimulation compared with the ₁-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 ₃-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 ₃-adrenoceptor-selective agonists.