title: Synthesis and characterization of selective dopamine D₂ receptor ligands using aripiprazole as the lead compound.
abstract: A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D(₂-like) dopamine receptors. These compounds also share structural elements with the classical D(₂-like) dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D₂ receptor subtype with high affinity (K(i) values < 0.3 nM), (b) exhibit >50-fold D₂ versus D₃ receptor binding selectivity and (c) be partial agonists at both the D₂ and D₃ receptor subtype.
authors.affiliation: Division of Radiological Sciences, Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 S. Kingshighway, St. Louis, MO 63110, USA.
authors.forename: Suwanna
authors.initials: S
authors.lastname: Vangveravong
authors.forename: Zhanbin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Michelle
authors.initials: M
authors.lastname: Taylor
authors.forename: Melissa
authors.initials: M
authors.lastname: Bearden
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.forename: Jinquan
authors.initials: J
authors.lastname: Cui
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000068180:Aripiprazole; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C561105:7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one; C561104:7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017480:Receptors, sigma; D000068180:Aripiprazole