Partial agonism of cardiac β-adrenoceptor Blocking Agents and Competitive Conformer-Receptor Occupancy

Abstract

Thc possibility that diffcrcnt conformations of a drug may control agonist and antagonist action upon biological receptors is explored in terms of a Competitive conformer-rcceptor occupancy model. Partial agonism is shown to bc a function of four parameters. the binding constants of the agonist and antagonist conformers. and the relativc populations of the conformers. Thc relation to Michaelis-Mcntcn formalism is defined. Application of thc model to thc partial agonist activity of phenoxypropanolamines on cardiac g-adrenoccptors suggests that a similar conformation of the compounds controls both agonist and antagonist action on the rcccptor. but thc agonist conforniation has ii marked additional conformational restriction and a displacement within the receptor to initiatc ii stimulatory response.