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Structure-based development of caged dopamine D(2)/D(3) receptor antagonists

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 neurotransmi...

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Autores principales: Gienger, Marie, Hübner, Harald, Löber, Stefan, König, Burkhard, Gmeiner, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972920/
https://www.ncbi.nlm.nih.gov/pubmed/31965029
http://dx.doi.org/10.1038/s41598-020-57770-9
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author Gienger, Marie
Hübner, Harald
Löber, Stefan
König, Burkhard
Gmeiner, Peter
author_facet Gienger, Marie
Hübner, Harald
Löber, Stefan
König, Burkhard
Gmeiner, Peter
author_sort Gienger, Marie
collection PubMed
description 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 D(3) receptor in complex with eticlopride, we have developed caged D(2)/D(3) receptor ligands by rational design. We initially found that eticlopride, a widely used D(2)/D(3) 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.
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spelling pubmed-69729202020-01-27 Structure-based development of caged dopamine D(2)/D(3) receptor antagonists Gienger, Marie Hübner, Harald Löber, Stefan König, Burkhard Gmeiner, Peter Sci Rep Article 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 D(3) receptor in complex with eticlopride, we have developed caged D(2)/D(3) receptor ligands by rational design. We initially found that eticlopride, a widely used D(2)/D(3) 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. Nature Publishing Group UK 2020-01-21 /pmc/articles/PMC6972920/ /pubmed/31965029 http://dx.doi.org/10.1038/s41598-020-57770-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Gienger, Marie
Hübner, Harald
Löber, Stefan
König, Burkhard
Gmeiner, Peter
Structure-based development of caged dopamine D(2)/D(3) receptor antagonists
title Structure-based development of caged dopamine D(2)/D(3) receptor antagonists
title_full Structure-based development of caged dopamine D(2)/D(3) receptor antagonists
title_fullStr Structure-based development of caged dopamine D(2)/D(3) receptor antagonists
title_full_unstemmed Structure-based development of caged dopamine D(2)/D(3) receptor antagonists
title_short Structure-based development of caged dopamine D(2)/D(3) receptor antagonists
title_sort structure-based development of caged dopamine d(2)/d(3) receptor antagonists
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972920/
https://www.ncbi.nlm.nih.gov/pubmed/31965029
http://dx.doi.org/10.1038/s41598-020-57770-9
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