Pluri-dimensionality of beta-adrenoceptor ligand signaling efficacy

【Author】

S.Galandrin;M.Bouvier;

【Abstract】

<正>Drug efficacy is classically considered an intrinsic property of a ligand/receptor couple. Accordingly, compounds are generally classified as agonists, inverse agonists or neutral antagonists for a given receptor. However, recent observations suggest that efficacy may also be influenced by the signalling cascade considered raising the possibility that drugs may have complex efficacy profiles toward the signalling activity of different effectors engaged by a unique receptor. To directly and systematically test this possibility, we assessed the ability of a panel of p-adrenergic ligands to modulate the activity of two effector systems, the adenylyl cyclase (AC) and the mitogen-activated protein kinase (MAPK) via β-adrenergic receptors (β-AR). Although some compounds diplayed simila r efficacies toward the two pathways, others showed complex efficacy profiles. For example, compounds that are inverse agonists for the AC activity, were found to be either agonists, neural antagonists or inverse agonists for the MAPK pathway. Reciprocally, agonist for the AC could be either agonists or neutral antagonist for MAPK. Given this complexity, we propose a Cartesian representation of the efficacies that takes into account the activities of the different effectors that can be engaged by a given receptor. In addition to challenge our classical vision of efficacy, the fact that the activity patterns of the ligands were different for the β1AR and the β2AR also shed new light on the concept of receptor subtype selectivity. Taken together, the results obtained are consistent with the notion that binding of different ligands can promote distinct conformational changes leading to specific signalling outcomes. Our data therefore demonstrate that efficacy is a pluridimensional parameter that can no longer be taken as an intrinsic characteristic of a ligand/receptor couple. This should have important implications for the future design of the screening assays used in drug discovery campaigns.

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