Models for Mechanism of Action

<p>Four models of small-molecule action are presented. In model 1, the small-molecule acts directly and uniquely as an antagonist of G-αq. In model 2 the small-molecule acts directly and uniquely as an agonist of the RGS protein's GAP activity. In models 3 and 4 (our preferred models), the small molecule interacts with both the RGS protein and G-αq, leading to an increased affinity of RGS for the complex and/or an “abortive” complex (failure of G-αq to recycle). All models lead to reduction of the GPCR signal through the activated G-αq.