Dataset Information

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.

SUBMITTER: Luedtke RR

PROVIDER: S-EPMC3526968 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds.

Luedtke Robert R RR Mishra Yogesh Y Wang Qi Q Griffin Suzy A SA Bell-Horner Cathy C Taylor Michelle M Vangveravong Suwanna S Dillon Glenn H GH Huang Ren-Qi RQ Reichert David E DE Mach Robert H RH

ACS chemical neuroscience 20121012 12

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 bindin ...[more]

PMID: 23259040

Similar Datasets

Project description:The D(2) dopamine receptor is an important therapeutic target for the treatment of psychotic, agitated, and abnormal behavioral states. To better understand the specific interactions of subtype-selective ligands with dopamine receptor subtypes, seven ligands with high selectivity (>120-fold) for the D(4) subtype of dopamine receptor were tested on wild-type and mutant D(2) receptors. Five of the selective ligands were observed to have 21-fold to 293-fold increases in D(2) receptor affinity when three non-conserved amino acids in TM2 and TM3 were mutated to the corresponding D(4) amino acids. The two ligands with the greatest improvement in affinity for the D(2) mutant receptor [i.e., 3-{[4-(4-iodophenyl) piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine (L-750,667) and 1-[4-iodobenzyl]-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine (RBI-257)] were investigated in functional assays. Consistent with their higher affinity for the mutant than for the wild-type receptor, concentrations of L-750,667 or RBI-257 that produced large reductions in the potency of quinpirole's functional response in the mutant did not significantly reduce quinpirole's functional response in the wild-type D(2) receptor. In contrast to RBI-257 which is an antagonist at all receptors, L-750,667 is a partial agonist at the wild-type D(2) but an antagonist at both the mutant D(2) and wild-type D(4) receptors. Our study demonstrates for the first time that the TM2/3 microdomain of the D(2) dopamine receptor not only regulates the selective affinity of ligands, but in selected cases can also regulate their function. Utilizing a new docking technique that incorporates receptor backbone flexibility, the three non-conserved amino acids that encompass the TM2/3 microdomain were found to account in large part for the differences in intermolecular steric contacts between the ligands and receptors. Consistent with the experimental data, this model illustrates the interactions between a variety of subtype-selective ligands and the wild-type D(2), mutant D(2), or wild-type D(4) receptors.

Dataset Information

Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds.

Publications

Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets