Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D4R) antagonists

Daniel E. Jeffries; Jonathan O. Witt; Andrea L. McCollum; Kayla J. Temple; Miguel A. Hurtado; Joel M. Harp; Anna L. Blobaum; Craig W. Lindsley; Corey R. Hopkins

doi:10.1016/j.bmcl.2016.10.049

Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D₄R) antagonists

Daniel E. Jeffries, Jonathan O. Witt, Andrea L. McCollum, Kayla J. Temple, Miguel A. Hurtado, Joel M. Harp, Anna L. Blobaum, Craig W. Lindsley, Corey R. Hopkins

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Herein, we report the synthesis and structure–activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D₄) antagonists. A series of compounds from this scaffold are highly potent against the D₄receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.

Original language	English (US)
Pages (from-to)	5757-5764
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2016.10.049
State	Published - 2016

Keywords

Addiction
Difluoropiperidine
Dopamine 4 receptor
PD-LIDs
Selectivity

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmcl.2016.10.049

Cite this

Jeffries, D. E., Witt, J. O., McCollum, A. L., Temple, K. J., Hurtado, M. A., Harp, J. M., Blobaum, A. L., Lindsley, C. W., & Hopkins, C. R. (2016). Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D₄R) antagonists. Bioorganic and Medicinal Chemistry Letters, 26(23), 5757-5764. https://doi.org/10.1016/j.bmcl.2016.10.049

Jeffries, DE, Witt, JO, McCollum, AL, Temple, KJ, Hurtado, MA, Harp, JM, Blobaum, AL, Lindsley, CW & Hopkins, CR 2016, 'Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D₄R) antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 23, pp. 5757-5764. https://doi.org/10.1016/j.bmcl.2016.10.049

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keywords = "Addiction, Difluoropiperidine, Dopamine 4 receptor, PD-LIDs, Selectivity",

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AU - Witt, Jonathan O.

AU - McCollum, Andrea L.

AU - Temple, Kayla J.

AU - Hurtado, Miguel A.

AU - Harp, Joel M.

AU - Blobaum, Anna L.

AU - Lindsley, Craig W.

AU - Hopkins, Corey R.

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KW - Addiction

KW - Difluoropiperidine

KW - Dopamine 4 receptor

KW - PD-LIDs

KW - Selectivity

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