Conformational effects on the activity of drugs .19. Synthesis and alpha-adrenergic activity of 2- and 6-methyl-substituted (3,4-dihydroxyphenyl)-3-piperidinols

Previous drug-receptor interaction mechanism studies at the molecular level of adrenergic drugs made it possible to construct two three-dimensional molecular models, A and B, using conformationally restrained cyclic analogues of natural catechol amines, including 3-(3,4-dihydroxyphenyl)-3-piperidinol (3-DPP, 3); these models offer useful information about the steric requirements for the direct activation of alpha(1)- and alpha(2)-adrenergic receptors, respectively. In order to grain further knowledge about the steric requirements of these receptors, we also synthesized 3-(3,4-dihydroxyphenyl)-c-2-methyl-r-3-piperidinol (2-MDPP, 8) and the 3-(3,4-dihydroxyphenyl)-c- and -t-6-methyl-r-3-piperidinols (6-MDPPs 9 and 10); these differ from the 3-DPP 3 used for the construction of the molecular models exclusively in the presence of a methyl in the 2 or 6 position of the heterocyclic ring. The configuration and conformation of the MDPPs 8-10 were assigned by H-1-NMR and IR studies, and confirmed by conformational analysis performed by means of theoretical calculations. The alpha(1)- and alpha(2)-adrenergic properties were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations. The results obtained made it possible to obtain a more refined steric definition of the A and B models