G-Protein/Receptor inhibitors as blockers of receptor signaling.

This paper describes the behavior of binding and functional receptor systems where an antagonist of the receptor/G protein binding reaction is added as a blocker of agonist-induced receptor function. For agonist radioligands, the reduction of G protein receptor interaction leads to a possible change in the binding affinity of the agonist radioligand to the receptor. Reciprocally, the allosteric cooperativity between the agonist and the G protein binding site antagonist (quantified by the factor γ) affects the potency of the G protein antagonist modulator; this model presents the various profiles that would be expected for modulators that reduce (γ = 0.01), have no effect on (γ = 1) and increase (γ = 100) the affinity of the agonist for the receptor. It will be seen that modulators that increase the affinity of the receptor for the agonist are the most potent antagonists and may attain a profile of some special negative allosteric modulators referred to as PAM antagonists. In all cases, these modulators will be inverse agonists of constitutive receptor activity. This model presents a strategy for the discovery of PAM antagonists for therapeutic blockade of physiological signaling.