Conformational effects on the activity of drugs. 11. Stereostructural models for the direct activation of the a- and ß-adrenergic receptor

Two kinds of cyclic analogues of norepinephrine (NE, 7) and isoprenaline (EO, 8), in which the C(l)-C(2) side chain of these amino alcohols is incorporated in its preferred conformation in the ring of the 2-(3,4-dihydroxyphenyl)- morpholines 9 and 10 (2-DPMs) and in the ring of the 3-(3,4-dihydroxyphenyl)-3-piperidinol1s1 and 12 (3-DPPs), respectively, were synthesized and assayed for their adrenergic activity on various isolated preparations. The 2-DPMs and the 3-DPPs showed an a- and &agonist activity comparable to that of NE and IS0 and to that of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-l-o1l3s a nd 14 (2-ADTNs), which represent another kind of semirigid analogue of NE and ISO. Through a comparison of the stereo structures of the compounds examined and of their pharmacological properties, it was possible to suggest a spatial situation in which the pharmacophoric groups of the adrenergic drugs examined (aryl moiety, amine nitrogen, and alcoholic or ethereal benzylic oxygen) should interact at the receptor site. This spatial situation corresponds to the one found in the preferred conformation of NE and ISO. It was also possible to construct two theoretical three-dimensional molecular models that provide information about steric requirements for the direct activation of a- and @-adrenoceptors, respectively.