CONFORMATIONAL EFFECTS ON THE ACTIVITY OF DRUGS .13. A REVISION OF PREVIOUSLY PROPOSED MODELS FOR THE ACTIVATION OF ALPHA-ADRENERGIC AND BETA-ADRENERGIC RECEPTORS

The alpha(1)-, alpha(2)-, beta(1)-, and beta(2)-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines 3 and 4 (2-DPMs), of the 3-( 3,4-dihydroxyphenyl)-3-piperidinols 5 and 6 (3-DPPs), and of the ns-2- amino-5,6-dihydroxytetrahydronaphthalen-1-ols 7 and 8 and the ns-2-ami no-6,7-dihydroxytetrahydronaphthalen-1-ols 9 and 10 (2-ADTNs) were eva luated in vitro both by radioligand binding assays and by functional t ests on isolated preparations and compared with those of norepinephrin e (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the stere ostructures of the compounds examined with their biopharmacological pr operties, it was possible to revise previously proposed molecular mode ls for the direct activation of alpha- and beta-adrenergic receptors. The revised models (A-C) provided information about the conformational requirements of adrenergic drugs, which substantially fit in with the results of several published studies involving conformationally-restr icted adrenoceptor agonists. The different position of the catecholic hydroxyl groups in model B, which refers to the alpha(2) receptors, an d in model C, which refers to the beta receptors, confirms the importa nce of the rotameric position of the aromatic ring of catecholamines i n the interaction with the alpha- and beta-adrenergic receptor.