Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT(2A) and 5-HT(2C) 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 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) = 0.92) and 5-HT(2C) (r(2) = 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*.
Egan
C
C
Department of Pharmacology & Neuroscience, Albany Medical College, Albany, New York 12208, USA.
Grinde
E
E
Dupre
A
A
Roth
B L
BL
Hake
M
M
Teitler
M
M
Herrick-Davis
K
K
D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D019204:GTP-Binding Proteins / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D010716:Phosphatidylinositols / Q000378:metabolism; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics*; D015398:Signal Transduction; D014162:Transfection; D014316:Tritium
D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D014316:Tritium; D019204:GTP-Binding Proteins