Attribution 4.0 International (CC BY 4.0)2022-07-112022-07-112021-05-26Lee, B., Taylor, M., Griffin, S. A., McInnis, T., Sumien, N., Mach, R. H., & Luedtke, R. R. (2021). Evaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands. Molecules (Basel, Switzerland), 26(11), 3182. https://doi.org/10.3390/molecules261131821420-3049https://hdl.handle.net/20.500.12503/31556N-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.http://creativecommons.org/licenses/by/4.0/D2-like dopamine receptorsD3 dopamine receptor subtypeG-protein coupled receptor (GPCR)bitopic ligandsdopamine receptor subtype selective ligandsAnimalsBenzamides / chemistryBinding, CompetitiveDopamine Agonists / chemistryDopamine Antagonists / chemistryDrug DesignHumansKineticsLevodopaLigandsMaleMiceMice, Inbred DBAParkinson Disease / drug therapyPiperazines / chemistryProtein BindingRatsReceptors, Dopamine D2 / chemistryReceptors, Dopamine D3 / chemistryArticleCopyright © 2021 by the authors.2611