N‐ARALKYL SUBSTITUTION INCREASES THE AFFINITY OF ADRENERGIC DRUGS FOR THE α‐ADRENOCEPTOR IN RAT LIVER

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Abstract
1 The α-adrenoceptor of rat liver plasma membranes was studied by use of the specificα-antagonist [3H]-dihydroergocryptine ([3H]-DHEC). Catecholamines and adrenergic compounds displayed an order of affinity that is typical of anα-receptor. Nevertheless, protokylol, a potent β-adrenoceptor agonist, exhibited a higher affinity than that of adrenaline forα-sites. This result might be due to its bulky substituent on the amino group. 2 Further displacement experiments between [3H]-DHEC and four pairs of drugs differently substituted on the amino group (isoprenaline vs Cc-25, orciprenaline vs fenoterol, AH 3474 vs labetalol, pindolol vs hydroxybenzylpindolol) provided evidence that N-alkyl substitution decreased the affinity forα-sites (20 μm < KD < 500 μm), whereas an N-aralkyl one increased the affinity (0.17 μm < KD < 4.6 μm). 3 It is concluded that a substitution on the amino group by a bulky, hydrophobic moiety enhances the affinity of drugs for the α-adrenoceptors.