Structure−Affinity Relationship Study on N-[4-(4-Arylpiperazin-1-yl)butyl]arylcarboxamides as Potent and Selective Dopamine D3 Receptor Ligands

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Abstract
The benzamide PB12 (N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide) (1), already reported as potent and selective dopamine D4 receptor ligand, has been modified searching for structural features that could lead to D3 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 (Ki = 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 D3 ligands (0.13 nM < Ki's < 4.97 nM) endowed with high selectivity over D2, D4, 5-HT1A, and α1 receptors. In addition, N-[4-[4-(2,3-dimethylphenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (27) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-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 11C labeling in the O-methyl position.
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