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Synthesis of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides and their evaluation as D3 receptor ligands

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Abstract

Cocaine (1) use disorder (CUD) is a major, unmet medical need. This tropane alkaloid is one of the most commonly abused recreational drugs. In 2018, there were over 5.5 million cocaine users. Therapeutic options capable of addressing this issue are limited, as there are no approved pharmacotherapies. The D3 dopamine receptor is a potential CUD therapeutic target that remains under active investigation. We have recently disclosed a series of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides typified by (8) that are potent D3 ligands that have moderate to high selectivity for D3 over D2. We have continued our exploration of this series of compounds in an effort to identify compounds with improved microsomal stability such as (12c).

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Acknowledgements

D1, D2, D3, D4, and D5 Ki determinations were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2018-00023-C (NIMH PDSP) [35]. The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. For experimental details please refer to the PDSP web site https://pdsp.unc.edu/ims/investigator/web/. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA, 194140, USA

    Benjamin E. Blass, Peng-Jen Chen & John C. Gordon

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Blass, B.E., Chen, PJ. & Gordon, J.C. Synthesis of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides and their evaluation as D3 receptor ligands. Med Chem Res 31, 735–748 (2022). https://doi.org/10.1007/s00044-022-02872-4

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