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High‐Affinity Agonist Binding Correlates with Efficacy (Intrinsic Activity) at the Human Serotonin 5‐HT2A and 5‐HT2C Receptors: Evidence Favoring the Ternary Complex and Two‐State Models of Agonist Action

Abstract: Many modern models of receptor‐G protein function assume that there is a direct relationship between high‐affinity agonist binding and efficacy. The validity of this assumption has been recently questioned for the serotonin 5‐HT2A receptor. We examined the intrinsic activities of various ligands in activating phosphoinositide hydrolysis and measured their respective binding affinities to the high‐ and low‐affinity states of the 5‐HT2C (VNV isoform) and 5‐HT2A receptors. Ligand binding affinities for the high‐affinity state of the receptors were determined using 1‐(4‐[125I]iodo‐2,5‐dimethoxyphenyl)‐2‐aminopropane, whereas [3H]mesulergine and N‐[3H]methylspiperone were used, in the presence of excess guanine nucleotide [guanosine 5′‐O‐(3‐thiotriphosphate)], to define binding to the low‐affinity state of the 5‐HT2C and 5‐HT2A receptors, respectively. Antagonists labeled the high‐ and low‐affinity states of each receptor with comparable affinities. Previously identified inverse agonists of the 5‐HT2C receptor behaved as silent antagonists in our systems even when the receptor was over‐expressed at a relatively high density. In contrast, the ability of agonists to bind differentially to the high‐ and low‐affinity states of the 5‐HT2A and 5‐HT2C receptors was highly correlated (r2= 0.86 and 0.96, respectively) with their intrinsic activities. These data suggest that high‐affinity agonist states can account for agonist efficacy at human 5‐HT2A or 5‐HT2C receptors without the need for considering additional transition or active states of the receptor‐ligand complex. The procedure described herein may expedite drug discovery efforts by predicting intrinsic activities of ligands solely from ligand binding assays.