Correlation between affinity and efficacy.

In a recent TiPS article [1xThe ligand paradox between affinity and efficacy: can you be there and not make a difference?. Kenakin, T. and Onaran, O. Trends Pharmacol. Sci. 2002; 23: 275–280Abstract | Full Text | Full Text PDF | PubMed | Scopus (98)See all References][1], Kenakin and Onaran presented a probabilistic model of protein conformation that describes efficacy and affinity as a function of agonist- and G-protein-induced perturbations of receptor states.In a simulation, the authors demonstrated that the model predicts a negative correlation between affinity and efficacy for different ligands acting in the same system, although homoscedacity in the model parameters allows for different agonists having identical efficacies with different affinities and identical affinities with different efficacies. The authors comment that the model contains too many parameters to use it to fit experimental data. Additionally, it seems very difficult to verify their simulated example experimentally because: (1) it would be practically impossible to test each compound in the same assay; and (2) a very large number of compounds would have to be synthesized and screened to reveal a correlation that is not overshadowed by the homoscedacity in the relationship as a result of between-assay variability. An alternative, perhaps more feasible, approach would be to use the inherent between-assay variability to test the predictions of the probabilistic model of receptor function with a single ligand. There are several examples in the literature indicating that it is indeed possible to reveal correlations between affinity and efficacy for a single agonist. For example, our analysis [2xAnalysis of inactivation experiments with the operational model of agonism yields correlated estimates of agonist affinity and efficacy. Van der Graaf, P.H. and Stam, W.B. J. Pharmacol. Toxicol. Meth. 1999; 41: 117–125Crossref | PubMed | Scopus (6)See all References][2] with the operational model of agonism [3xOperational models of pharmacological agonism. Black, J.W. and Leff, P. Proc. R. Soc. Lond. B. 1983; 220: 141–162Crossref | PubMedSee all References][3] of noradrenaline responses in rat small mesenteric arteries before and after phenoxybenzamine treatment revealed a highly significant, negative correlation between operational affinity (pKA) and efficacy (log τ), consistent with the predictions of the probability model. A similar conclusion can be inferred [2xAnalysis of inactivation experiments with the operational model of agonism yields correlated estimates of agonist affinity and efficacy. Van der Graaf, P.H. and Stam, W.B. J. Pharmacol. Toxicol. Meth. 1999; 41: 117–125Crossref | PubMed | Scopus (6)See all References][2] from data reported for the effects of carbachol and pilocarpine in guinea-pig ileum [4xGraphical assessment of the operational model of agonist action. Henry, A. et al. FASEB J. 1992; 6: A1561See all References][4], 5-HT in rabbit aorta [5xEstimation of agonist affinity and efficacy by direct, operational model-fitting. Leff, P. et al. J. Pharmacol. Meth. 1990; 23: 225–237Crossref | PubMed | Scopus (61)See all References][5], 5-methylfurmethide in guinea-pig trachea [6xApplication of the operational model of agonism to establish conditions when functional antagonism may be used to estimate agonist dissociation constants. Leff, P. et al. Br. J. Pharmacol. 1985; 85: 655–663Crossref | PubMedSee all References][6] and phenylephrine in rat tail artery [7xEndothelial modulation of α1-adrenoceptor contractile responses in the tail artery of spontaneous hypertensive rats. Tabernero, A. et al. Br. J. Pharmacol. 1996; 119: 765–771Crossref | PubMedSee all References][7]. Although it cannot be excluded that such observations are due to a statistical rather than a pharmacological phenomenon and reflect the issue of over-parameterization inherent to mechanistic models of agonism [2xAnalysis of inactivation experiments with the operational model of agonism yields correlated estimates of agonist affinity and efficacy. Van der Graaf, P.H. and Stam, W.B. J. Pharmacol. Toxicol. Meth. 1999; 41: 117–125Crossref | PubMed | Scopus (6)See all References][2], it is tempting to suggest that they are examples of experimental evidence for the conformational selection hypothesis of agonist action.