Structural and conformational features determining selective signal transduction in the beta 3-adrenergic receptor.

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.