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

Abstract In a previous study we found that certain 3-phenylpiperidines (PPEs, 5) display a good activity at α 2 -adrenergic receptors (α 2 -AR ), whereas they are completely inactive at α 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 β 1 - and β 2 -AR. The methyl groups present on the aromatic ring of 5a are found, albeit in a different position, on the phenyl of α 2 -adrenergic agonists with arylimidazolidine and arylimidazole structures. As such PPE 5a provided a unique template for the design of α 2 -AR ligands. On the basis of these premises, we synthesized all the possible dimethylphenyl-substituted isomers of PPE 5a . Their activity on α 1 - and α 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 α 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.