Comparison of the Bindingand Functional Propertiesof Two Structurally Different D2 Dopamine Receptor Subtype SelectiveCompounds

摘要

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 affinityof these two compounds was evaluated using (a) wild type human D2and D3 receptors and (b) a panel of chimeric D2/D3 dopamine receptors.Computer-assisted modeling techniques were used to dock these compoundsto the human D2 and D3 dopamine receptor subtypes. It is hoped thatthese studies on D2 receptor selective ligands will be useful in thefuture design of (a) receptor selective ligands used to define thefunction of D2-like receptor subtypes, (b) novel pharmacotherapeuticagents, and/or (c) in vitro and in vivo imaging agents.