title: Structural and conformational features determining selective signal transduction in the beta 3-adrenergic receptor.
abstract: With respect to the beta 1- and beta 2-adrenergic receptors (ARs), the beta 3-AR induces specific physiological effects in a few target tissues and exhibits atypical pharmacological properties that distinguish it unambiguously from its counterparts. Therefore, the beta 3-AR represents a suitable model to study the molecular mechanism responsible for receptor subtype selectivity and specificity. Potent beta 3-AR ligands newly characterized in Chinese hamster ovary cells expressing the beta 3-AR were also evaluated in Chinese hamster ovary cells expressing beta 1- and beta 2-ARs and were classified into three groups according to their pharmacological properties. Among the beta 1/beta 2/beta 3 agonists BRL 37344 and LY 79771 exhibit beta 3 selectivity in stimulating adenylyl cyclase; among the beta 1/beta 2 antagonists displaying beta 3 agonistic effects ICI 201651 exhibits beta 3-AR binding selectivity, whereas among the beta 1/beta 2/beta 3 antagonist class bupranolol is the most efficient (but not selective) beta 3-AR antagonist. The structures of these ligands were simulated and compared using computer-generated molecular modeling. Structure-activity relationship analysis indicates that potent or selective beta 3-AR compounds, in addition to possessing a pharmacophore common to all beta-AR ligands, contain a long and bulky alkylamine substituent moiety, which is able to adopt and exchange extended and stacked conformations. Computerized three-dimensional models of the beta 1-, beta 2-, and beta 3-AR binding sites show that more bulky amino acid side chains point inside the groove of the beta 1 and beta 2 sites, compared with the beta 3 site, in a region implicated in signal processing. The long alkylamine chain of compounds behaving as beta 1/beta 2 antagonists and beta 3 agonists may thus adopt either a stacked conformation in the encumbered beta 1- and beta 2-AR sites, leading to antagonistic effects, or an extended conformation in the less encumbered beta 3 site, thus interacting with specific residues implicated in signal transduction.
authors.affiliation: Institut Cochin de Génétique Moléculaire, CNRS-UPR 0415, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Blin
authors.forename: L
authors.initials: L
authors.lastname: Camoin
authors.forename: B
authors.initials: B
authors.lastname: Maigret
authors.forename: A D
authors.initials: AD
authors.lastname: Strosberg
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011943:Receptors, Adrenergic, beta / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins