Role of the benzylic hydroxyl group of adrenergic catecholamines in eliciting α-adrebergic activity. Synthesis and α1- and α2-adrenergic activity of 3-phenyl-3-piperidinols and their desoxy analogs

Article abstract of DOI:10.1016/0223-5234(96)88306-1

In order to contribute to the definition of the role played by the benzylic hydroxyl group of adrenergic catecholamines in eliciting α-adrenergic activity, certain 3-phenyl-3-piperidinols (PPOs, 4) and their corresponding desoxy 3-phenylpiperidine analogs (PPEs, 6) were synthesized and tested for their α₁- and α₂-adrenergic activity by means of functional tests on isolated preparations.As regards the α₁-adrenergic activity, the values of the activity indices of the cyclic catecholic compounds (PPO 4a and PPE 6a) indicate that the benzylic hydroxyl does notplay an essential role, provided that the other two active groups are in the pharmacophoric conformation.However, the fact that none of the other non-catecholic cyclic analogs are active on the α₁-receptor does not allow us to generalize this observation.As regards the α₂-adrenergic activity, the high values of the activity indices of PPEs 6, compared with those of the corresponding 1-phenyl-2-aminoethanols (PAEs,3), PPPOs (4) and 2-phenylethylamines (PEAs,5), confirm that when the aromatic moiety and the amino group are constrained into the pharmacophoric relationship, the presence of the alcoholic hydroxyl is not only unnecessary for the purposes of the expression of the activity at the level of the α₂-adrenoceptor, but often has negative effect. adrenergic drug / 3-phenyl-3-piperidinol / 3-phenylpiperidine / 1-phenyl-2-aminoethanol / 2-phenylethylamine / α₁-adrenergic agonist activity / α₂-adrenergic agonist activity