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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...

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Autores principales: Kilian, Jonas, Ozenil, Marius, Millard, Marlon, Fürtös, Dorka, Maisetschläger, Verena, Holzer, Wolfgang, Wadsak, Wolfgang, Hacker, Marcus, Langer, Thierry, Pichler, Verena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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