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

• Main Authors: Boeun Lee, Michelle Taylor, Suzy A. Griffin, Tamara McInnis, Nathalie Sumien, Robert H. Mach, Robert R. Luedtke
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: Molecules
• Subjects: D2-like dopamine receptors; D3 dopamine receptor subtype; G-protein coupled receptor (GPCR); dopamine receptor subtype selective ligands; bitopic ligands
• Online Access: https://www.mdpi.com/1420-3049/26/11/3182
• ISSN: 1420-3049

<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.