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Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M(1) Antagonists
Due to their important role in mediating a broad range of physiological functions, muscarinic acetylcholine receptors (mAChRs) have been a promising target for therapeutic and diagnostic applications alike; however, the list of truly subtype-selective ligands is scarce. Within this work, we have ide...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8879200/ https://www.ncbi.nlm.nih.gov/pubmed/35215360 http://dx.doi.org/10.3390/ph15020248 |
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author | Kilian, Jonas Ozenil, Marius Millard, Marlon Fürtös, Dorka Maisetschläger, Verena Holzer, Wolfgang Wadsak, Wolfgang Hacker, Marcus Langer, Thierry Pichler, Verena |
author_facet | Kilian, Jonas Ozenil, Marius Millard, Marlon Fürtös, Dorka Maisetschläger, Verena Holzer, Wolfgang Wadsak, Wolfgang Hacker, Marcus Langer, Thierry Pichler, Verena |
author_sort | Kilian, Jonas |
collection | PubMed |
description | Due to their important role in mediating a broad range of physiological functions, muscarinic acetylcholine receptors (mAChRs) have been a promising target for therapeutic and diagnostic applications alike; however, the list of truly subtype-selective ligands is scarce. Within this work, we have identified a series of twelve 4,4’-difluorobenzhydrol carbamates through a rigorous docking campaign leveraging commercially available amine databases. After synthesis, these compounds have been evaluated for their physico–chemical property profiles, including characteristics such as HPLC-logD, tPSA, logBB, and logPS. For all the synthesized carbamates, these characteristics indicate the potential for BBB permeation. In competitive radioligand binding experiments using Chinese hamster ovary cell membranes expressing the individual human mAChR subtype hM(1)-hM(5), the most promising compound 2 displayed a high binding affinitiy towards hM(1)R (1.2 nM) while exhibiting modest-to-excellent selectivity versus the hM(2-5)R (4–189-fold). All 12 compounds were shown to act in an antagonistic fashion towards hM1R using a dose-dependent calcium mobilization assay. The structural eligibility for radiolabeling and their pharmacological and physico–chemical property profiles render compounds 2, 5, and 7 promising candidates for future position emission tomography (PET) tracer development. |
format | Online Article Text |
id | pubmed-8879200 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88792002022-02-26 Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M(1) Antagonists Kilian, Jonas Ozenil, Marius Millard, Marlon Fürtös, Dorka Maisetschläger, Verena Holzer, Wolfgang Wadsak, Wolfgang Hacker, Marcus Langer, Thierry Pichler, Verena Pharmaceuticals (Basel) Article Due to their important role in mediating a broad range of physiological functions, muscarinic acetylcholine receptors (mAChRs) have been a promising target for therapeutic and diagnostic applications alike; however, the list of truly subtype-selective ligands is scarce. Within this work, we have identified a series of twelve 4,4’-difluorobenzhydrol carbamates through a rigorous docking campaign leveraging commercially available amine databases. After synthesis, these compounds have been evaluated for their physico–chemical property profiles, including characteristics such as HPLC-logD, tPSA, logBB, and logPS. For all the synthesized carbamates, these characteristics indicate the potential for BBB permeation. In competitive radioligand binding experiments using Chinese hamster ovary cell membranes expressing the individual human mAChR subtype hM(1)-hM(5), the most promising compound 2 displayed a high binding affinitiy towards hM(1)R (1.2 nM) while exhibiting modest-to-excellent selectivity versus the hM(2-5)R (4–189-fold). All 12 compounds were shown to act in an antagonistic fashion towards hM1R using a dose-dependent calcium mobilization assay. The structural eligibility for radiolabeling and their pharmacological and physico–chemical property profiles render compounds 2, 5, and 7 promising candidates for future position emission tomography (PET) tracer development. MDPI 2022-02-18 /pmc/articles/PMC8879200/ /pubmed/35215360 http://dx.doi.org/10.3390/ph15020248 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kilian, Jonas Ozenil, Marius Millard, Marlon Fürtös, Dorka Maisetschläger, Verena Holzer, Wolfgang Wadsak, Wolfgang Hacker, Marcus Langer, Thierry Pichler, Verena Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M(1) Antagonists |
title | Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M(1) Antagonists |
title_full | Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M(1) Antagonists |
title_fullStr | Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M(1) Antagonists |
title_full_unstemmed | Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M(1) Antagonists |
title_short | Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M(1) Antagonists |
title_sort | design, synthesis, and biological evaluation of 4,4’-difluorobenzhydrol carbamates as selective m(1) antagonists |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8879200/ https://www.ncbi.nlm.nih.gov/pubmed/35215360 http://dx.doi.org/10.3390/ph15020248 |
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