Novel M2-selective, Gi-biased agonists of muscarinic acetylcholine receptors

Alena Randáková, Dominik Nelic, Dana Ungerová, Peter Nwokoye, Qiwen Su, Vladimír Doležal, Esam E. El-Fakahany, John Boulos, Jan Jakubík

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Purpose: More than 30% of currently marketed medications act via GPCRs. Thus, GPCRs represent one of the most important pharmacotherapeutic targets. In contrast to traditional agonists activating multiple signalling pathways, agonists activating a single signalling pathway represent a new generation of drugs with increased specificity and fewer adverse effects. Experimental Approach: We have synthesized novel agonists of muscarinic ACh receptors and tested their binding and function (on levels of cAMP and inositol phosphates) in CHO cells expressing individual subtypes of muscarinic receptors, primary cultures of rat aortic smooth muscle cells and suspensions of digested native tissues from rats. Binding of the novel compounds to M2 receptors was modelled in silico. Key Results: Two of the tested new compounds (1-(thiophen-2-ylmethyl)-3,6-dihydro-2H-pyridinium and 1-methyl-1-(thiophen-2-ylmethyl)-3,6-dihydro-2H-pyridinium) only inhibited cAMP synthesis in CHO cells, primary cultures, and native tissues, with selectivity for M2 muscarinic receptors and displaying bias towards the Gi signalling pathway at all subtypes of muscarinic receptors. Molecular modelling revealed interactions with the orthosteric binding site in a way specific for a given agonist followed by agonist-specific changes in the conformation of the receptor. Conclusions and Implications: The identified compounds may serve as lead structures in the search for novel non-steroidal and non-opioid analgesics acting via M2 and M4 muscarinic receptors with reduced side effects associated with activation of the phospholipase C signalling pathway.

Original languageEnglish (US)
Pages (from-to)2073-2089
Number of pages17
JournalBritish Journal of Pharmacology
Volume177
Issue number9
DOIs
StatePublished - May 1 2020

Bibliographical note

Funding Information:
This work was supported by the Czech Academy of Sciences Support RVO:67985823, the Grant Agency of the Czech Republic Grant 17-16182S, and the Physical Science Department at Barry University. We thank Dr. Ba??kov? (Department of Biomaterials and Tissue Engineering, Institute of Physiology CAS) for providing us with primary cell culture of smooth muscle cells. Access to computing and storage facilities owned by parties and projects contributing to the Czech National Grid Infrastructure MetaCentrum provided under the programme ?Projects of Large Research, Development, and Innovations Infrastructures? (CESNET LM2015042) is greatly appreciated.

Funding Information:
This work was supported by the Czech Academy of Sciences Support RVO:67985823, the Grant Agency of the Czech Republic Grant 17‐16182S, and the Physical Science Department at Barry University. We thank Dr. Bačáková (Department of Biomaterials and Tissue Engineering, Institute of Physiology CAS) for providing us with primary cell culture of smooth muscle cells. Access to computing and storage facilities owned by parties and projects contributing to the Czech National Grid Infrastructure MetaCentrum provided under the programme “Projects of Large Research, Development, and Innovations Infrastructures” (CESNET LM2015042) is greatly appreciated.

Publisher Copyright:
© 2020 The British Pharmacological Society

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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