title: Stereoselectivity for interactions of agonists and antagonists at mouse, rat and human beta3-adrenoceptors.
abstract: This study examines the stereoselectivity profile of recombinant mouse, rat and human beta(3)-adrenoceptors expressed in Chinese Hamster Ovary (CHO-K1) cells using radioligand binding, in comparison with endogenously expressed beta(3)-adrenoceptors mediating relaxation responses in mouse ileum. The enantiomeric ratios for several beta-adrenoceptor agonists and antagonists at the cloned mouse, rat and human beta(3)-adrenoceptor were less than those reported at the cloned beta(1)-/beta(2)-adrenoceptor but higher than those reported in previous studies. The degree of stereoselectivity was relatively low for the agonists isoprenaline and noradrenaline but higher for antagonists and, in particular, tertatolol and propranolol. In mouse ileum, stereoselectivity of propranolol and tertatolol was observed under beta(1)-/beta(2)-adrenoceptor blockade. The (-)-enantiomers of propranolol and tertatolol were more effective at antagonism of (-)-isoprenaline-mediated relaxation of mouse ileum than their (+)-enantiomers. The recombinant mouse, rat and human beta(3)-adrenoceptors display stereoselective interactions for agonists and antagonists similar to the stereoselective profile of beta(3)-adrenoceptors in mouse ileum. The degree of stereoselectivity varied between species and the human beta(3)-adrenoceptor displayed higher affinities and enantiomeric ratios than the mouse or rat beta(3)-adrenoceptors.
authors.affiliation: Department of Pharmacology, Monash University, Victoria 3800, Australia.
authors.forename: Ben D
authors.initials: BD
authors.lastname: Popp
authors.forename: Dana S
authors.initials: DS
authors.lastname: Hutchinson
authors.forename: Bronwyn A
authors.initials: BA
authors.lastname: Evans
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Summers
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D007082:Ileum / Q000378:metabolism; D008297:Male; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D013045:Species Specificity; D013237:Stereoisomerism
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D022702:Receptors, Adrenergic, beta-3