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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.

SUBMITTER: Tolentino KT

PROVIDER: S-EPMC8966054 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists.

Tolentino Kirsten T KT Mashinson Viktoriya V Vadukoot Anish K AK Hopkins Corey R CR

Bioorganic & medicinal chemistry letters 20220210

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 characteri ...[more]

PMID: 35151866

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