Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

Abstract

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. KEYWORDS: Dopamine receptors, binding selectivity, functional selectivity, GPCR structure, D2-like dopamine receptors, GPCR model building, ligand−receptor docking T here are three dopaminergic pathways in the brain: the nigrostriatal pathway, the mesocorticolimbic pathway, and the tuberoinfundibular pathway. These pathways are involved in movement coordination, cognition, emotion, memory, reward, and regulation of prolactin secretion. Alterations in the dopaminergic pathways are thought to be involved in the pathogenesis of neurological, neuropsychiatric, and hormonal disorders. 1−6 Modulation of the dopaminergic pathways is also thought to occur as a consequence of acute or chronic abuse of pyschostimulants. 7,8 Previous studies have defined two types of dopamine receptors, the D1-like (D1 and D5 subtypes) and D2-like (D2, D3, and D4 subtypes) receptors. D1-like receptors are linked to the activation of adenylyl cyclase via coupling to the Gs/Golf class of G proteins. 9 Stimulation of the D2-like receptors results in coupling with the Gi/Go class of G proteins, leading to the inhibition of adenylyl cyclase activity. 10,11 Agonist activation of D2-like receptors can also lead to (a) activation of G-protein-coupled inward rectifying potassium (GIRK) channels, (b) stimulation of mitogenesis, (c) an increase in...

Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs

“…In the docked D2 structure, the indole-piperazine portion of 1 occupies the orthosteric site, and the indole N-H group forms a hydrogen bond with S193 5.42 ( Fig. 1e ), which is consistent with D2 docking of aripiprazole 38 , 39 , and with β1AR crystal structure pose of the indole-piperazine 37 . Additionally, we confirmed 1 ’s docking pose at TM5 serine mutants, where compound 1 ’s affinity ( Supplementary Fig.…”

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds

“…The studies presented in this communication represent continuation of our previous work on the development and pharmacological characterization of novel ligands that exhibit either D2 vs. D3 (Huang et al, 2013;Luedtke et al, 2012;Vangveravong et al, 2011Vangveravong et al, , 2010Vangveravong et al, , 2006 or D3 vs. D2 Tu et al, 2013Tu et al, , 2011Wang et al, 2010;Chu et al, 2005) dopamine receptor binding selectivity. It also extends our previous studies designed to use these dopamine D2-like receptor subtype selective compounds in vivo in an attempt to define the role of these two structurally and pharmacologically similar receptor subtypes in animal models of neurological and neuropsychiatric disorders (Kumar et al, 2009;Weber et al, 2009;Nolan et al, 2013;Rangel-Barajas et al, 2014), as well as psychostimulant abuse (Cheung et al, 2012.…”

Dopamine Receptors and Neurodegeneration

“…The activation of ERK1/2 has been also observed in a variety of cell lines, including in HEK-293 cells, COS-7 cells and C6 glioma cells, for this signaling pathway, D2Rs and D4Rs also display some differences in the intensity of ERK/MAPK activation compared to D3Rs using highly selective compounds [51,52]. On the other hand, the complex GPCRs-β-arrestin also activates ERK/MAPK once the receptor is internalized [53].…”