Structure-based development of caged dopamine D2/D3 receptor antagonists

Gienger M, Hübner H, Löber S, König B, Gmeiner P (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 10

Article Number: 829

Journal Issue: 1

DOI: 10.1038/s41598-020-57770-9

Abstract

Dopamine is a neurotransmitter of great physiological relevance. Disorders in dopaminergic signal transduction are associated with psychiatric and neurological pathologies such as Parkinson’s disease, schizophrenia and substance abuse. Therefore, a detailed understanding of dopaminergic neurotransmission may provide access to novel therapeutic strategies for the treatment of these diseases. Caged compounds with photoremovable groups represent molecular tools to investigate a biological target with high spatiotemporal resolution. Based on the crystal structure of the D3 receptor in complex with eticlopride, we have developed caged D2/D3 receptor ligands by rational design. We initially found that eticlopride, a widely used D2/D3 receptor antagonist, was photolabile and therefore is not suitable for caging. Subtle structural modification of the pharmacophore led us to the photostable antagonist dechloroeticlopride, which was chemically transformed into caged ligands. Among those, the 2-nitrobenzyl derivative 4 (MG307) showed excellent photochemical stability, pharmacological behavior and decaging properties when interacting with dopamine receptor-expressing cells.

Authors with CRIS profile

Involved external institutions

Universität Regensburg Germany (DE)

How to cite

APA:

Gienger, M., Hübner, H., Löber, S., König, B., & Gmeiner, P. (2020). Structure-based development of caged dopamine D2/D3 receptor antagonists. Scientific Reports, 10(1). https://doi.org/10.1038/s41598-020-57770-9

MLA:

Gienger, Marie, et al. "Structure-based development of caged dopamine D2/D3 receptor antagonists." Scientific Reports 10.1 (2020).

BibTeX: Download