NDLI: Evaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands

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Evaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands

Content Provider	MDPI
Author	Lee, Boeun Taylor, Michelle Griffin, Suzy McInnis, Tamara Sumien, Nathalie Mach, Robert Luedtke, Robert
Copyright Year	2021
Description	N-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 N-phenylpiperazine analogs were evaluated. Compound 6a was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound 6a 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 6a 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.
Starting Page	3182
e-ISSN	14203049
DOI	10.3390/molecules26113182
Journal	Molecules
Issue Number	11
Volume Number	26
Language	English
Publisher	MDPI
Publisher Date	2021-05-26
Access Restriction	Open
Subject Keyword	Molecules Medicinal Chemistry D2-like Dopamine Receptors D3 Dopamine Receptor Subtype G-protein Coupled Receptor (gpcr) Dopamine Receptor Subtype Selective Ligands Bitopic Ligands
Content Type	Text
Resource Type	Article

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