Synthesis and in vitro binding of N-phenyl piperazine analogs as potential dopamine D3 receptor ligands

A series of N-(2-methoxyphenyl)piperazine and N-(2,3-dichlorophenyl)piperazine analogs were prepared and their affinities for dopamine D-2, D-3, and D-4 receptors were measured in vitro. Binding studies were also conducted to determine if the compounds bound to sigma (sigma(1) and sigma(2)) and serotonin (5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7) receptors. The results of the current study revealed a number of compounds (12b, 12c, 12e, and 12g) having a high affinity for D-3 (K-i at D-3 receptors ranging from 0.3 to 0.9 nM) versus D-2 (K-i at D-2 receptors ranging from 40 to 53 nM) receptors and a log P value indicating that they should readily cross the blood brain barrier (log P = 2.6-3.5). All of the compounds evaluated in this study had a high affinity for serotonin 5-HT1A receptors. These compounds may be useful as probes for studying the behavioral pharmacology of the dopamine D-3 receptor, as well as lead compounds for the development of radiotracers for studying D-3 receptor regulation in vivo with the functional imaging technique, positron emission tomography. (C) 2004 Elsevier Ltd. All rights reserved.