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

Robert T. Luedtke, Yogesh Mishra, Qi Wang, Suzy A. Griffin, Cathy Bell-Horner, Michelle Taylor, Suwanna Vangveravong, Glenn H. Dillon, Ren-Qi Huang, David E. Reichert, Robert H. MacH

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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.

Original languageEnglish
Pages (from-to)1050-1062
Number of pages13
JournalACS Chemical Neuroscience
Volume3
Issue number12
DOIs
StatePublished - 19 Dec 2012

Fingerprint

Dopamine D3 Receptors
Dopamine D2 Receptors
Assays
Adenylyl Cyclases
G Protein-Coupled Inwardly-Rectifying Potassium Channels
Ligands
GTP-Binding Proteins
Docks
1-((5-methoxy-1H-indol-3-yl)methyl)-4-(4-(methylthio)phenyl)piperidin-4-ol
Chemical activation
Imaging techniques

Keywords

  • D2-like dopamine receptors
  • Dopamine receptors
  • GPCR model building
  • GPCR structure
  • binding selectivity
  • functional selectivity
  • ligand-receptor docking

Cite this

Luedtke, Robert T. ; Mishra, Yogesh ; Wang, Qi ; Griffin, Suzy A. ; Bell-Horner, Cathy ; Taylor, Michelle ; Vangveravong, Suwanna ; Dillon, Glenn H. ; Huang, Ren-Qi ; Reichert, David E. ; MacH, Robert H. / Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds. In: ACS Chemical Neuroscience. 2012 ; Vol. 3, No. 12. pp. 1050-1062.
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keywords = "D2-like dopamine receptors, Dopamine receptors, GPCR model building, GPCR structure, binding selectivity, functional selectivity, ligand-receptor docking",
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Luedtke, RT, Mishra, Y, Wang, Q, Griffin, SA, Bell-Horner, C, Taylor, M, Vangveravong, S, Dillon, GH, Huang, R-Q, Reichert, DE & MacH, RH 2012, 'Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds', ACS Chemical Neuroscience, vol. 3, no. 12, pp. 1050-1062. https://doi.org/10.1021/cn300142q

Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds. / Luedtke, Robert T.; Mishra, Yogesh; Wang, Qi; Griffin, Suzy A.; Bell-Horner, Cathy; Taylor, Michelle; Vangveravong, Suwanna; Dillon, Glenn H.; Huang, Ren-Qi; Reichert, David E.; MacH, Robert H.

In: ACS Chemical Neuroscience, Vol. 3, No. 12, 19.12.2012, p. 1050-1062.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds

AU - Luedtke, Robert T.

AU - Mishra, Yogesh

AU - Wang, Qi

AU - Griffin, Suzy A.

AU - Bell-Horner, Cathy

AU - Taylor, Michelle

AU - Vangveravong, Suwanna

AU - Dillon, Glenn H.

AU - Huang, Ren-Qi

AU - Reichert, David E.

AU - MacH, Robert H.

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N2 - 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.

AB - 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.

KW - D2-like dopamine receptors

KW - Dopamine receptors

KW - GPCR model building

KW - GPCR structure

KW - binding selectivity

KW - functional selectivity

KW - ligand-receptor docking

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