Conformational effects on the activity of drugs part 21 - N-n-propyl-substitute 3-(dimethylphenyl)piperidines display novel discriminative propertiesbetween dopamine receptor subtypes: Synthesis and receptor binding studies

3-Phenylpiperidines (PPEs) have been thoroughly investigated in view of the ir interesting dopaminergic activity, and the N-n-propyl substitution has b een suggested as the most effective among several PPEs differently substitu ted on the phenyl ring. In previous studies, we found that the dimethyl sub stitution on the phenyl ring of N-unsubstituted PPEs provided compounds act ive toward alpha(2)-adrenergic receptors (alpha(2)-ARs), which proved to po ssess interesting selectivity properties. The high degree of homology betwe en the binding domains of a2-ARs and D-4-dopaminergic receptors (D-4-DARs) prompted us to verify whether this kind of substitution on the aromatic rin g might prove to be active against retinal DARs of the D-4 subtype. On the basis of these premises, we synthesized the dimethylphenyl-substituted PPEs 4a-f, in which an n-propyl chain is present on the aminic nitrogen. Radiol igand binding assays on bovine retina and striatum membranes for D-1-like a nd D-2-like DARs indicated that PPEs 4a, 4b, and 4f possess a high affinity and selectivity for the D-4-DAR subtype of bovine retina.