N-n-Propyl-substituted 3-(dimethylphenyl)piperidines display novel discriminative properties between dopamine receptor subtypes: synthesis and receptor binding studies.

3-Phenylpiperidines (PPEs) have been thoroughly investigated in view of their interesting dopaminergic activity, and the N-n-propyl substitution has been suggested as the most effective among several PPEs differently substituted on the phenyl ring. In previous studies, we found that the dimethyl substitution on the phenyl ring of N-unsubstituted PPEs provided compounds active toward alpha2-adrenergic receptors (alpha2-ARs), which proved to possess interesting selectivity properties. The high degree of homology between the binding domains of alpha2-ARs and D4-dopaminergic receptors (D4-DARs) prompted us to verify whether this kind of substitution on the aromatic ring might prove to be active against retinal DARs of the D4 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. Radioligand binding assays on bovine retina and striatum membranes for D1-like and D2-like DARs indicated that PPEs 4a, 4b, and 4f possess a high affinity and selectivity for the D4-DAR subtype of bovine retina.