CONFORMATIONAL EFFECTS ON THE ACTIVITY OF DRUGS .19. SYNTHESIS AND ALPHA-ADRENERGIC ACTIVITY OF 2-METHYL-SUBSTITUTED 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-dime nsional molecular models, A and B, using conformationally restrained c yclic analogues of natural catechol amines, including 3-(3,4-dihydroxy phenyl)-3-piperidinol (3-DPP, 3); these models offer useful informatio n about the steric requirements for the direct activation of alpha(1)- and alpha(2)-adrenergic receptors, respectively. In order to grain fu rther knowledge about the steric requirements of these receptors, we a lso 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-piperi dinols (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 configurat ion 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 pro perties were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations. The results obtained ma de it possible to obtain a more refined steric definition of the A and B models.