Estimation of the efficacy and affinity of the beta 2-adrenoceptor agonist salmeterol in guinea-pig trachea.
1. We have attempted to estimate the affinity and efficacy of the new beta 2-adrenoceptor agonist salmeterol in the guinea-pig isolated trachea and to compare these estimates with those obtained for salbutamol. 2. The kinetics of the relaxation to salmeterol were considerably slower than those to salbutamol and the responses were poorly defined. Nevertheless, in experiments employing a cumulative curve design both salmeterol and salbutamol exhibited partial agonist behaviour. Operational model-fitting of these data indicated that the intrinsic efficacies of the two agonists were indistinguishable but that salmeterol had an affinity (pKA = 7.4) some 30 fold greater than salbutamol (pKA = 5.9). 3. Single dose experiments, using maximally effective concentrations of salmeterol or salbutamol were carried out in an attempt to quantify more reliably the relative efficacies of the two agonists. In these experiments salbutamol was found to have an efficacy (2.5) approximately 3 fold greater than that of salmeterol (0.8). 4. Full/partial agonist interaction studies were carried out to provide another estimate of the affinity of salmeterol. Isoprenaline and adrenaline were employed as full agonists in these experiments and the affinity (pKB) estimates obtained for salmeterol against these agonists were 7.3 and 7.4 respectively. These affinity estimates were similar to the pKA value (7.4) obtained by operational model-fitting. 5. Salmeterol has slightly lower efficacy (3 fold) but markedly greater affinity (30 fold) than salbutamol at beta 2-receptors. The slightly lower efficacy of salmeterol is unlikely to have clinical implications for this drug as a bronchodilator beta 2-adrenoceptor agonist in asthma.
Department of Pharmacology, Fisons plc, Leicestershire.
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Dougall
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Harper
D M
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Jackson
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Leff
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D000068299:Salmeterol Xinafoate; D014132:Trachea / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000068299:Salmeterol Xinafoate; D007545:Isoproterenol; D000420:Albuterol