Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists

Kirsten T. Tolentino; Viktoriya Mashinson; Anish K. Vadukoot; Corey R. Hopkins

doi:10.1016/j.bmcl.2022.128615

Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists

Kirsten T. Tolentino, Viktoriya Mashinson, Anish K. Vadukoot, Corey R. Hopkins

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

4 Scopus citations

Abstract

The dopamine receptor 4 (D₄R) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the D₄R in the modulation of this network and its subsequent involvement in L-DOPA induced dyskinesias in Parkinson's disease. As part of our continued effort in the discovery of novel D₄R antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as D₄R antagonists. We report several D₄R selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported D₄R antagonists.

Original language	English (US)
Article number	128615
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	61
DOIs	https://doi.org/10.1016/j.bmcl.2022.128615
State	Published - Apr 1 2022

Keywords

Antagonists
Benzyloxypiperidine
D4R
Dopamine 4 receptor
Parkinson's disease

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2022.128615

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title = "Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists",

abstract = "The dopamine receptor 4 (D4R) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the D4R in the modulation of this network and its subsequent involvement in L-DOPA induced dyskinesias in Parkinson's disease. As part of our continued effort in the discovery of novel D4R antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as D4R antagonists. We report several D4R selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported D4R antagonists.",

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AU - Tolentino, Kirsten T.

AU - Mashinson, Viktoriya

AU - Vadukoot, Anish K.

AU - Hopkins, Corey R.

PY - 2022/4/1

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AB - The dopamine receptor 4 (D4R) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the D4R in the modulation of this network and its subsequent involvement in L-DOPA induced dyskinesias in Parkinson's disease. As part of our continued effort in the discovery of novel D4R antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as D4R antagonists. We report several D4R selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported D4R antagonists.

KW - Antagonists

KW - Benzyloxypiperidine

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KW - Dopamine 4 receptor

KW - Parkinson's disease

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Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists

Abstract

Keywords

ASJC Scopus subject areas

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