title: Beta-adrenoceptor subtype activities of trimetoquinol derivatives: biochemical studies on human beta-adrenoceptors expressed in chinese hamster ovary cells.
abstract: The beta-adrenoceptor activities of trimetoquinol (TMQ) isomers and selected derivatives were evaluated on human beta-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 beta(1)-, beta(2)-, and beta(3)-adrenoceptor subtypes, respectively. In radioligand binding assays, (-)-TMQ exhibited 123-, 331-, and 5-fold greater affinity than (+)-TMQ for beta(1)-, beta(2)-, and beta(3)-adrenoceptor subtypes, respectively. (-)-TMQ and (+/-)-TMQ activated the human beta(3)-adrenoceptor with an 8.2- and 3.4-fold greater efficacy, respectively, than the reference beta-adrenoceptor agonist (-)-isoproterenol (efficacy = 1). The 3',5'-diiodo analogs of TMQ were partial agonists of the beta(2)-adrenoceptor relative to (-)-isoproterenol, and their potencies were 5- to 10-fold higher at the beta(3)-adrenoceptor as compared with beta(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 beta(2)-adrenoceptor and exhibited beta(3)-adrenoceptor-selective stimulation compared with the beta(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 beta(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 beta(3)-adrenoceptor-selective agonists.
authors.affiliation: Division of Pharmacology, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Konkar
authors.forename: S S
authors.initials: SS
authors.lastname: Vansal
authors.forename: G
authors.initials: G
authors.lastname: Shams
authors.forename: P F
authors.initials: PF
authors.lastname: Fraundorfer
authors.forename: W P
authors.initials: WP
authors.lastname: Zheng
authors.forename: V I
authors.initials: VI
authors.lastname: Nikulin
authors.forename: J
authors.initials: J
authors.lastname: De Los Angeles
authors.forename: R H
authors.initials: RH
authors.lastname: Fertel
authors.forename: D D
authors.initials: DD
authors.lastname: Miller
authors.forename: D R
authors.initials: DR
authors.lastname: Feller
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002396:Catechols / Q000737:chemistry; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000145:classification / Q000502:physiology*; D014213:Tretoquinol / Q000031:analogs & derivatives / Q000378:metabolism*
chemical_list: D000318:Adrenergic beta-Agonists; D002396:Catechols; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D014213:Tretoquinol; D007545:Isoproterenol; C034221:catechol