Agonist high and low affinity state ratios predict drug intrinsic activityand a revised ternary complex mechanism at serotonin 5-HT2A and 5-HT2C receptors

The ternary complex model as applied to G-protein coupled receptors (GPCR) predicts that an agonist binds with low affinity (K-L) to the free receptor (R), leading to an agonist/receptor/G-protein complex. This ternary comple x displays high agonist affinity (K-H), resulting in signal transduction. C lassical dogma states that, the ratio K-L/K-H predicts intrinsic activity o f drugs: the higher the ratio the higher the intrinsic activity. This model was based on studies in which K-L and K-H were indirectly determined by co mputer analyses of antagonist radioligand binding data. In order to investi gate the relationship of K-L, K-H, and intrinsic activity for agonists at 5 -HT2A and 5-HT2C receptors, we utilized H-3-agonist and H-3-antagonist radi oligands to directly determine K-H and K-L. Comparisons of the log K-L/K-H ratios and intrinsic activities of drugs for stimulating intracellular phos phatidylinositol (PI) hydrolysis revealed a strong correlation for 5-HT2A ( r(2) = 0.92) and 5-HT2C (r(2) = 0.96) receptors. The data were fit to compu ter simulations based on the original ternary complex model and the revised ternary complex model in which an activated state of the receptor (R*) exi sts in equilibrium with the resting state of the receptor (R). Data produce d for both 5-HT2A and 5-HT2C receptors were better-fitted to a revised tern ary complex model, rather than the classical ternary complex model. These d ata support a revised model for the molecular events coupling GPCR to activ ation of G-proteins and indicate that a strong correlation between the K-L/ K-H ratio and intrinsic activity for agonist action at GPCR is consistent w ith the existence of R*. (C) 2000 Wiley-Liss, Inc.