Synthesis and α-adrenergic activity of 2- and 6-methyl-substituted (3,4-dihydroxyphenyl)-3-piperidinols

Summary 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 catecholamines, including 3-(3,4-dihydroxyphenyl)-3-piperidinol (3-DPP, 3 ); these models offer useful information about the steric requirements for the direct activation of α 1 - and α 2 -adrenergic receptors, respectively. In order to gain 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 1 H-NMR and IR studies, and confirmed by conformational analysis performed by means of theoretical calculations. The α 1 - and α 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.