Quantitative description of α₂‐adrenergic potency in terms of receptor affinity and intrinsic activity

Abstract

Attempts were made to describe quantitatively peripheral as well as central α2‐adrenergic potency as a linear combination of affinity for and intrinsic activity at α2‐adrenoceptors within a series of 16 α‐adrenergic agonists, of the imidazolidine type. Central α2‐adrenergic potency was quantified as the ability of the compounds to decrease mean arterial pressure of pentobarbitone‐anaesthetized normotensive rats by 20% following intravenous administration. Peripheral α2‐adrenergic potency was measured in pithed normotensive rats as the inhibitory activity on stimulation‐induced tachycardia. Central and peripheral α2‐adrenergic potencies were linearly correlated upon including logP′ (octanol/buffer partition coefficient, pH 7.4, 37°C), showing the different accessibility of the two α2‐adrenoceptor populations. Affinity of the imidazolidines for α2‐adrenoceptors was determined by the displacement of 3H‐clonidine from its specific binding sites in membranes from rat brain. The linear relationships between peripheral and central α2‐adrenergic potency on the one hand and affinity for α2‐adrenoceptors with or without the addition of logP′ on the other hand were significantly improved by incorporation of a term standing for receptor activation, i.e. intrinsic activity at α2‐adrenoceptors. The results support current concepts in receptor theory stating that only when both efficacy and affinity are known, can the activity of the agonist be predicted with reasonable certainty.