Synthesis and α-adrenergic and I1-imidazoline activity of 3-phenylpiperidines dimethyl-substituted on the phenyl ring

In a previous study we found that certain 3-phenylpiperidines (PPEs, 5) display a good activity at alpha(2)-adrenergic receptors (alpha(2)-AR), whereas they are completely inactive at alpha(1)-AR. The PPEs 5 are conformationally restricted analogs of the corresponding adrenergic drug with a phenylethylamine structure (PAEs, 4) in which the benzylic hydroxyl group characteristic of the adrenergic catecholamines is not present. The most interesting of the PPEs proved to be the 3-(3,4-dimethylphenyl) substituted compound (5a) which had been found to be essentially inactive at beta(1)- and beta(2)-AR. The methyl groups present on the aromatic ring of 5a are found, albeit in a different position, on the phenyl of alpha(2)-adrenergic agonists with arylimidazolidine and arylimidazole structures. As such PPE 5a provided a unique template for the design of alpha(2)-AR ligands. On the basis of these premises, we synthesized all the possible dimethylphenyl-substituted isomers of PPE 5a. Their activity on alpha(1)- and alpha(2)-AR and on I-1-imidazoline receptors (IR) was evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparation. Two selected PPEs, 5a and 5f, were also tested for their affinity on alpha(2)-AR subtypes. Conformational studies were carried out by means of theoretical calculations, in order to rationalise the results of pharmacological tests at the molecular level. (C) Elsevier, Paris.