Conformational effects on the activity of drugs. 13. A revision of previously proposed models for the activation of a- and ß-adrenergic receptors

The al-,a z-&, -,a nd &-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines3 and 4 (2-DPMs), of the 3-(3,4-dihydroxyphenyl)-3-piperidinol5s and 6 (3-DPPs), and of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen- 1-01s 7 and 8 and the tram-2-amino-6,7-dihydroxytetrahydronaphthalen-l-o9l asn d 10 (2-ADTNs) were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations and compared with those of norepinephrine (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the,stereostructures of the compounds examined with their biopharmacological properties, it was possible to revise previously proposed molecular models for the direct activation of a- and @-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-restricted adrenoceptor agonists. The different position of the catecholic hydroxyl groups in model B, which refers to the a2 receptors, and in model C, which refers to the B receoton. confirms the imwrtance of the rotameric Dosition of the aromatic ring of catecholamines in the interaction with ihe a: and &adrenergic receptor.