Interactions of agonists and antagonists with beta-adrenergic receptors

The interactions of agonists and antagonists with beta-adrenergic receptors appear to be fundamentally different. Antagonists only occupy the receptor while agonists bind to the receptor and induce a specific conformational change. The excellent correlation between the efficacy of full or partial agonists and the magnitude of the changes in the thermodynamic parameters associated with the binding of these compounds suggests that this conformational change is related to the ability of various drugs to stimulate adenylate cyclase. In most instances it is difficult to distinguish an agonist from an antagonist using the in vitro binding of radiolabeled ligands. The thermodynamic analysis described here represents one example of a situation in which agonists and antagonists can be distinguished using in vitro binding techniques. The complexities of agonist interactions with beta-adrenergic receptors are also clearly seen in studies of binding to intact cells and in direct studies using radiolabeled agonists. In the former studies it appeared that there were marked changes in the properties of the receptor that occurred during the 60 min that are required for the binding of IHYP to beta-adrenergic receptors on L6 myoblasts to reach equilibrium. These changes make it difficult to analyze the affinity of the receptor for agonists using intact cells. Finally, the complexities of agonist interactions with the beta-adrenergic receptor are also seen in direct binding studies with radiolabeled agonists. The curvilinear Scatchard plots and the complicated dissociation kinetics attest to this complexity. The importance of the formation of a hypothetical ternary complex between hormone, receptor, and guanine nucleotide-binding regulatory protein is now becoming appreciated. The existence of other components of this system will remain an important subject for future investigation. In any case, it is clear that a full understanding of this system will require the use of not only radiolabeled agonists and antagonists but also of both broken and intact cells.