title: Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands.
abstract: A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors.
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Mishra
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Reichert
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Maninder
authors.initials: M
authors.lastname: Malik
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States; Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States; Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States. Electronic address: rmach@mail.med.upenn.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D001665:Binding Sites; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D008024:Ligands; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D014230:Triazoles; D044282:Receptor, Serotonin, 5-HT1A; D050638:Receptors, Dopamine D4
keywords: Dopamine D(3) receptor selective ligands; Dopamine receptors; Molecular modeling; Triazole