title: Synthesis and in vitro binding of N-phenyl piperazine analogs as potential dopamine D3 receptor ligands.
abstract: 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-HT(1A), 5-HT(2A), 5-HT(2B), 5-HT(2C), 5-HT(3), 5-HT(4), 5-HT(5), 5-HT(6), and 5-HT(7)) 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-HT(1A) 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.
authors.affiliation: Department of Radiology, Division of Radiological Sciences, Washington University School of Medicine, Campus Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO 63110, USA.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Chu
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McElveen
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.forename: Michelle
authors.initials: M
authors.lastname: Taylor
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D002460:Cell Line; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D017480:Receptors, sigma / Q000378:metabolism
chemical_list: C493593:DRD3 protein, human; D015259:Dopamine Agents; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017480:Receptors, sigma; D000077489:Piperazine; D000262:Adenylyl Cyclases