title: Analysis of receptor inactivation experiments with the operational model of agonism yields correlated estimates of agonist affinity and efficacy.
abstract: The aim of this study was to evaluate whether the operational model of agonism can yield independent estimates of agonist affinity (pK(A)) and efficacy (log tau) when Furchgott's method of irreversible receptor inactivation is employed. For this purpose, the interaction between noradrenaline and phenoxybenzamine was studied in rat small mesenteric artery using a paired-curve design. Phenoxybenzamine pretreatment produced a significant rightward shift and depression of the upper asymptote of the noradrenaline concentration-effect (E/[A]) curve. Although the operational model of agonism appeared to provide an adequate fit of the individual E/[A] curves, a highly significant correlation was found between the estimates of pK(A )and log tau (r = -0.80, p < 0.0001), inconsistent with the assumption that affinity and efficacy are independent parameters (best line fit: pK(A) = -0.96 x log tau + 6.75). The pK(A) and log tau estimates were not correlated with either the pEC50s of the control curves or upper asymptotes of the phenoxybenzamine-treated curves. Simulations showed that the correlation between affinity and efficacy can be explained by the effect on the outcome of the analysis of random errors in the response measurements. Therefore, although in theory the operational model of agonism should provide independent estimates of agonist affinity and efficacy, this is unlikely to be the case with experimental data.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, The Netherlands. piet_van_der_graaf@sandwich.pfizer.com
authors.forename: P H
authors.initials: PH
authors.lastname: Van der Graaf
authors.forename: W B
authors.initials: WB
authors.lastname: Stam
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D010643:Phenoxybenzamine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018340:Receptors, Adrenergic, alpha-1; D010643:Phenoxybenzamine; D009638:Norepinephrine