title: The relative contribution of affinity and efficacy to agonist activity: organ selectivity of noradrenaline and oxymetazoline with reference to the classification of drug receptors.
abstract: Oxymetazoline demonstrated a pronounced organ selectivity, when compared to noradrenaline, by being a potent full agonist in rat anococcygeus muscle and a partial agonist in rat vas deferens. Responses of rat anococcygeus muscles to oxymetazoline were relatively more sensitive to antagonism by phenoxybenzamine (Pbz) an alkylating alpha-adrenoceptor antagonist. Therefore, although oxymetazoline was more potent than noradrenaline in this tissue, after Pbz (0.3 microM for 10 min), the responses to oxymetazoline were completely inhibited while those to noradrenaline were only partially inhibited. Schild analysis with phentolamine, corynanthine, prazosin and yohimbine indicated no alpha-adrenoceptor heterogeneity within the rat anococcygeus muscle or between this tissue and rat vas deferens. Measurement of agonist Kd values and Schild analysis of oxymetazoline antagonism of responses to noradrenaline (after alkylation) confirmed the homogeneity of alpha-adrenoceptors with respect to these two agonists. The above profiles of activity would be predicted if oxymetazoline had a higher affinity but lower efficacy than noradrenaline. Experimentally this was confirmed when it was found that oxymetazoline had 5 times the affinity but 0.2 to 0.3 times the efficacy of noradrenaline. These results serve as a caveat to the use of selective receptor desensitization and/or selective receptor alkylation (or protection from alkylation) as means of differentiating drug receptors. Theoretical modelling and these experimental results indicate that high affinity/low efficacy agonists are much more sensitive to receptor coupling. The implications for therapeutic selectivity could be important in that high affinity/low efficacy agonists theoretically have a much greater potential for organ selectivity.
mesh_terms: D000818:Animals; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009928:Organ Specificity; D010109:Oxymetazoline / Q000494:pharmacology*; D010643:Phenoxybenzamine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000145:classification / Q000187:drug effects; D011955:Receptors, Drug / Q000145:classification / Q000187:drug effects*; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; D011955:Receptors, Drug; D010643:Phenoxybenzamine; D010109:Oxymetazoline; D009638:Norepinephrine