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Leopoldo M, Berardi F, Colabufo NA, De Giorgio P, Lacivita E, Perrone R, Tortorella V: Structure-affinity relationship study on N-[4-(4-arylpiperazin-1-yl) butyl] arylcarboxamides as potent and selective dopamine D (3) receptor ligands. J Med Chem. 2002 Dec 19;45(26):5727-35.
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 D (3) affinity (K (i) = 145 and 31 nM, respectively). Intermediate alkyl chain elongation in compounds 1, 6, and 13 improved binding affinity for the D (3) receptor and decreased the D (4) 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 < K (i)'s < 4.97 nM) endowed with high selectivity over D (2), D (4), 5-HT (1A), and alpha (1) 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-benzofuranca rboxamide (41) appear to be valuable candidates for positron emission tomography (PET) because of their affinity values, lipophilicity properties, and liability of (11) C labeling in the O-methyl position. |
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