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. 2022 Apr 1:61:128615.
doi: 10.1016/j.bmcl.2022.128615. Epub 2022 Feb 10.

Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists

Kirsten T Tolentino  1 , Viktoriya Mashinson  1 , Anish K Vadukoot  1 , Corey R Hopkins  2
Affiliations

Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists

Kirsten T Tolentino et al. Bioorg Med Chem Lett. .

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.

Keywords: Antagonists; Benzyloxypiperidine; D4R; Dopamine 4 receptor; Parkinson’s disease.

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Figures

Figure 1.
Figure 1.
Figure 2.
Figure 2.
Ligand interaction poses generated using Glide docking software (PDB: 5WIU). A. Compound 1, B. Compound 8c, C. Compound 9j, D. Compound 11d.
Scheme 1.
Scheme 1.
Synthesis of the 3-(S)- or 4-ether piperidines, 8, 9, or 11.
See this image and copyright information in PMC

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