STRUCTURAL AND CONFORMATIONAL FEATURES DETERMINING SELECTIVE SIGNAL-TRANSDUCTION IN THE BETA-3-ADRENERGIC RECEPTOR

With respect to the beta1- and beta2-adrenergic receptors (ARs), the b eta3-AR induces specific physiological effects in a few target tissues and exhibits atypical pharmacological properties that distinguish it unambiguously from its counterparts. Therefore, the beta3-AR represent s a suitable model to study the molecular mechanism responsible for re ceptor subtype selectivity and specificity. Potent beta3-AR ligands ne wly characterized in Chinese hamster ovary cells expressing the beta3- AR were also evaluated in Chinese hamster ovary cells expressing beta1 - and beta2-ARs and were classified into three groups according to the ir pharmacological properties. Among the beta1 /beta2/beta3 agonists B RL 37344 and LY 79771 exhibit beta3 selectivity in stimulating adenyly l cyclase; among the beta1 /beta2 antagonists displaying beta3 agonist ic effects ICI 201651 exhibits beta3-AR binding selectivity, whereas a mong the beta1 /beta2/beta3 antagonist class bupranolol is the most ef ficient (but not selective) beta3-AR antagonist. The structures of the se ligands were simulated and compared using computer-generated molecu lar modeling. Structure-activity relationship analysis indicates that potent or selective beta3-AR compounds, in addition to possessing a ph armacophore common to all beta-AR ligands, contain a long and bulky al kylamine substituent moiety, which is able to adopt and exchange exten ded and stacked conformations. Computerized three-dimensional models o f the beta1-, beta2-, and beta3-AR binding sites show that more bulky amino acid side chains point inside the groove of the beta1 and beta2 sites, compared with the beta3 site, in a region implicated in signal processing. The long alkylamine chain of compounds behaving as beta1/b eta2 antagonists and beta3 agonists may thus adopt either a stacked co nformation in the encumbered beta1- and beta2-AR sites, leading to ant agonistic effects, or an extended conformation in the less encumbered beta3 site, thus interacting with specific residues implicated in sign al transduction.