Kinetic Benefit(s) of Allosteric Receptor Blockade by Positive Allosteric Modulator Antagonists

Abstract

This paper discusses how targeted pharmacologic experiments can elucidate the mechanism of allosteric receptor inhibitors (NAMs) to identify NAMs that may have exceptionally useful properties and target residence times in vivo. Specifically, experiments can be done to identify positive allosteric modulator (PAM) antagonists, NAMs that increase the affinity of the receptor for the agonist but decrease agonist efficacy. These molecules would be predicted to have long receptor offset times in vivo (in the presence of ambient concentrations of agonist) and favorable receptor residence times for therapy and also selectively target agonist prebound receptors. Flux analysis is used to demonstrate the salient properties of PAM antagonists and their favorable pharmacodynamic effects for blocking physiological signals.