title: Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds.
abstract: We previously reported on the synthesis of substituted phenyl-4-hydroxy-1-piperidyl indole analogues with nanomolar affinity at D2 dopamine receptors, ranging from 10- to 100-fold selective for D2 compared to the D3 dopamine receptor subtype. More recently, we evaluated a panel of aripiprazole analogues, identifying several analogues that also exhibit D2 vs D3 dopamine receptor binding selectivity. These studies further characterize the intrinsic efficacy of the compound with the greatest binding selectivity from each chemical class, 1-((5-methoxy-1H-indol-3-yl)methyl)-4-(4-(methylthio)phenyl)piperidin-4-ol (SV 293) and 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (SV-III-130s), using an adenylyl cyclase inhibition assay, a G-protein-coupled inward-rectifying potassium (GIRK) channel activation assay, and a cell based phospho-MAPK (pERK1/2) assay. SV 293 was found to be a neutral antagonist at D2 dopamine receptors using all three assays. SV-III-130s is a partial agonist using an adenylyl cyclase inhibition assay but an antagonist in the GIRK and phospho ERK1/2 assays. To define the molecular basis for the binding selectivity, the affinity of these two compounds was evaluated using (a) wild type human D2 and D3 receptors and (b) a panel of chimeric D2/D3 dopamine receptors. Computer-assisted modeling techniques were used to dock these compounds to the human D2 and D3 dopamine receptor subtypes. It is hoped that these studies on D2 receptor selective ligands will be useful in the future design of (a) receptor selective ligands used to define the function of D2-like receptor subtypes, (b) novel pharmacotherapeutic agents, and/or (c) in vitro and in vivo imaging agents.
authors.affiliation: The Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA. robert.luedtke@unthsc.edu
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Mishra
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Suzy A
authors.initials: SA
authors.lastname: Griffin
authors.forename: Cathy
authors.initials: C
authors.lastname: Bell-Horner
authors.forename: Michelle
authors.initials: M
authors.lastname: Taylor
authors.forename: Suwanna
authors.initials: S
authors.lastname: Vangveravong
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Dillon
authors.forename: Ren-Qi
authors.initials: RQ
authors.lastname: Huang
authors.forename: David E
authors.initials: DE
authors.lastname: Reichert
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3