Structure-affinity relationship study on N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides as potent and selective dopamine D3 receptor Ligands

The benzamide PB12 (N-[2-[4-(4-chlorophenyl)piperazin-1-yl] ethyl]-3-methoxybenzamide) (1), already reported as potent and selective dopamine D-4 receptor ligand, has been modified searching for structural features that could lead to D-3 receptor affinity. Changes in the aromatic ring linked to N-1 piperazine ring led to the identification of 2-methoxyphenyl and 2,3-dichlorophenyl derivatives (compounds 6 and 13) displaying moderate D3 affinity (K-i = 145 and 31 nM, respectively). Intermediate alkyl chain elongation in compounds 1, 6, and 13 improved binding affinity for the D3 receptor and decreased the D4 affinity (compounds 18-26). Among these latter compounds, the N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (19) was further modified with the replacement or of the 2,3-dichlorophenyl moiety (compounds 27-30) or of the 3-methoxyphenyl ring (compounds 31-41). In this way, we identified several high-affinity D-3 ligands (0.13 nM < Ki's < 4.97 nM) endowed with high selectivity over D-2, D-4, 5-HTA, and alpha(1) receptors. In addition, N-[4-[4-(2,3-dimethylphenyl)piperazin-1-yllbutyl]-3-methoxybenzamide (27) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yllbutyl]-7-methoxy-2-benzofurancarboxamide (41) appear to be valuable candidates for positron emission tomography (PET) because of their affinity values, lipophilicity properties, and liability of C-11 labeling in the O-methyl position.