title: Biochemical activities of trimetoquinol analogs at human beta(1)- and beta(3)-adrenergic receptors.
abstract: The biochemical activities of trimetoquinol (TMQ) analogs were evaluated at the human beta(1)- and beta(3)-adrenergic receptor (AR) subtypes expressed in Chinese hamster ovary cells. In radioligand binding assays, the 1-benzyl iodine-substituted analogs exhibited higher binding affinities at both beta(1)- and beta(3)-AR subtype as compared to TMQ. In cAMP accumulation assays, these analogs exhibited high potencies at both beta(1)- and beta(3)-AR. The 3',5'-diiodo-4'-amino analog of TMQ was the most potent beta(3)-AR agonist, 17-fold more potent at the beta(3)-AR versus the beta(1)-AR. Masking of the 6,7-dihydroxy group of the catechol ring of 3',5'-diiodo-4'-acetamido analog of TMQ, a potent beta(1)- and beta(3)-AR agonist, abolished activity at both beta-AR subtypes. Furthermore, substitution of a strong electron withdrawing group such as the trifluoromethyl moiety at the 1-benzyl ring of TMQ dramatically decreased potency at beta(1)- and beta(3)-AR compared to TMQ. Replacement of the 1-benzyl ring of TMQ with a naphthalene ring did not alter affinity but reduced potency of resulting 1-naphthylmethyl and 2-naphthylmethyl analogs at beta(1)- and beta(3)-AR compared to TMQ. Our results define the structural and electronic properties of substituents on TMQ necessary for potent activation of beta(1)- and beta(3)-AR and suggest that further modifications of the 1-benzyl iodine-substituted analogs may yield potent beta(3)-AR agonists.
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Konkar
authors.forename: V I
authors.initials: VI
authors.lastname: Nikulin
authors.forename: J
authors.initials: J
authors.lastname: De Los Angeles
authors.forename: S S
authors.initials: SS
authors.lastname: Hong
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 / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011869:Radioligand Assay; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014213:Tretoquinol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; D018342:Receptors, Adrenergic, beta-1; D022702:Receptors, Adrenergic, beta-3; D000242:Cyclic AMP; D014213:Tretoquinol