N-ARALKYL SUBSTITUTION INCREASES THE AFFINITY OF ADRENERGIC-DRUGS FOR THE ALPHA-ADRENOCEPTOR IN RAT-LIVER

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. 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). It is concluded that a substitution on the amino group by a bulky, hydrophobic moiety enhances the affinity of drugs for the α‐adrenoceptors. 1979 British Pharmacological Society