Evaluation of Substituted <i>N</i>-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands
<i>N-</i>phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compo...
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doaj-a3182d90e87b4adc85a60f89cdb4f1712021-06-01T01:11:10ZengMDPI AGMolecules1420-30492021-05-01263182318210.3390/molecules26113182Evaluation of Substituted <i>N</i>-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective LigandsBoeun Lee0Michelle Taylor1Suzy A. Griffin2Tamara McInnis3Nathalie Sumien4Robert H. Mach5Robert R. Luedtke6Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center-Fort Worth, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center-Fort Worth, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center-Fort Worth, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center-Fort Worth, Fort Worth, TX 76107, USADepartment of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center-Fort Worth, Fort Worth, TX 76107, USA<i>N-</i>phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted <i>N</i>-phenylpiperazine analogs were evaluated. Compound <b>6a</b> was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound <b>6a</b> was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound <b>6a</b> was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson’s disease.https://www.mdpi.com/1420-3049/26/11/3182D2-like dopamine receptorsD3 dopamine receptor subtypeG-protein coupled receptor (GPCR)dopamine receptor subtype selective ligandsbitopic ligands |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Boeun Lee Michelle Taylor Suzy A. Griffin Tamara McInnis Nathalie Sumien Robert H. Mach Robert R. Luedtke |
spellingShingle |
Boeun Lee Michelle Taylor Suzy A. Griffin Tamara McInnis Nathalie Sumien Robert H. Mach Robert R. Luedtke Evaluation of Substituted <i>N</i>-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands Molecules D2-like dopamine receptors D3 dopamine receptor subtype G-protein coupled receptor (GPCR) dopamine receptor subtype selective ligands bitopic ligands |
author_facet |
Boeun Lee Michelle Taylor Suzy A. Griffin Tamara McInnis Nathalie Sumien Robert H. Mach Robert R. Luedtke |
author_sort |
Boeun Lee |
title |
Evaluation of Substituted <i>N</i>-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands |
title_short |
Evaluation of Substituted <i>N</i>-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands |
title_full |
Evaluation of Substituted <i>N</i>-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands |
title_fullStr |
Evaluation of Substituted <i>N</i>-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands |
title_full_unstemmed |
Evaluation of Substituted <i>N</i>-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands |
title_sort |
evaluation of substituted <i>n</i>-phenylpiperazine analogs as d3 vs. d2 dopamine receptor subtype selective ligands |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2021-05-01 |
description |
<i>N-</i>phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted <i>N</i>-phenylpiperazine analogs were evaluated. Compound <b>6a</b> was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound <b>6a</b> was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound <b>6a</b> was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson’s disease. |
topic |
D2-like dopamine receptors D3 dopamine receptor subtype G-protein coupled receptor (GPCR) dopamine receptor subtype selective ligands bitopic ligands |
url |
https://www.mdpi.com/1420-3049/26/11/3182 |
work_keys_str_mv |
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