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

A series of N-(2-methoxyphenyl)piperazine and N-(2,3-dichlorophenyl)piperazine analogs were prepared and their affinities for dopamine D2, D3, and D4 receptors were measured in vitro. Binding studies were also conducted to determine if the compounds bound to sigma (σ1 and σ2) 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 D3 (Ki at D3 receptors ranging from 0.3 to 0.9 nM) versus D2 (Ki at D2 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 D3 receptor, as well as lead compounds for the development of radiotracers for studying D3 receptor regulation in vivo with the functional imaging technique, positron emission tomography.