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

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dc.creatorLee, Boeun
dc.creatorTaylor, Michelle
dc.creatorGriffin, Suzy A.
dc.creatorMcInnis, Tamara
dc.creatorSumien, Nathalie
dc.creatorMach, Robert H.
dc.creatorLuedtke, Robert R.
dc.creator.orcid0000-0002-0077-9873 (Sumien, Nathalie)
dc.creator.orcid0000-0001-8469-2371 (Luedtke, Robert R.)
dc.date.accessioned2022-07-11T15:29:25Z
dc.date.available2022-07-11T15:29:25Z
dc.date.issued2021-05-26
dc.description.abstractN-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.
dc.description.sponsorshipThis research was funded by National Institute on Drug Abuse, grant number, DA029840 (R.H.M.) and DA023957 (R.R.L.).
dc.identifier.citationLee, 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/molecules26113182
dc.identifier.issn1420-3049
dc.identifier.issue11
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31556
dc.identifier.volume26
dc.publisherMDPI
dc.relation.urihttps://doi.org/10.3390/molecules26113182
dc.rights.holderCopyright © 2021 by the authors.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceMolecules
dc.subjectD2-like dopamine receptors
dc.subjectD3 dopamine receptor subtype
dc.subjectG-protein coupled receptor (GPCR)
dc.subjectbitopic ligands
dc.subjectdopamine receptor subtype selective ligands
dc.subject.meshAnimals
dc.subject.meshBenzamides / chemistry
dc.subject.meshBinding, Competitive
dc.subject.meshDopamine Agonists / chemistry
dc.subject.meshDopamine Antagonists / chemistry
dc.subject.meshDrug Design
dc.subject.meshHumans
dc.subject.meshKinetics
dc.subject.meshLevodopa
dc.subject.meshLigands
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshMice, Inbred DBA
dc.subject.meshParkinson Disease / drug therapy
dc.subject.meshPiperazines / chemistry
dc.subject.meshProtein Binding
dc.subject.meshRats
dc.subject.meshReceptors, Dopamine D2 / chemistry
dc.subject.meshReceptors, Dopamine D3 / chemistry
dc.titleEvaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands
dc.typeArticle
dc.type.materialtext

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