Agonist high and low affinity state ratios predict drug intrinsic activity and a revised Ternary complex mechanism at serotonin 5-HT2A and 5-HT2C receptors
✍ Scribed by Christina Egan; Ellinor Grinde; Ann Dupre; Bryan L. Roth; Michael Hake; Milt Teitler; Katharine Herrick-Davis
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 151 KB
- Volume
- 35
- Category
- Article
- ISSN
- 0887-4476
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✦ Synopsis
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 complex displays high agonist affinity (K H ), resulting in signal transduction. Classical dogma states that the ratio K L /K H predicts intrinsic activity of 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 computer analyses of antagonist radioligand binding data. In order to investigate the relationship of K L , K H , and intrinsic activity for agonists at 5-HT 2A and 5-HT 2C receptors, we utilized 3 H-agonist and 3 H-antagonist radioligands 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 phosphatidylinositol (PI) hydrolysis revealed a strong correlation for 5-HT 2A (r 2 ϭ 0.92) and 5-HT 2C (r 2 ϭ 0.96) receptors. The data were fit to computer simulations based on the original ternary complex model and the revised ternary complex model in which an activated state of the receptor (R*) exists in equilibrium with the resting state of the receptor (R). Data produced for both 5-HT 2A and 5-HT 2C receptors were better-fitted to a revised ternary complex model, rather than the classical ternary complex model. These data support a revised model for the molecular events coupling GPCR to activation 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 with the existence of R*.