Novel M-2-selective, G(i)-biased agonists of muscarinic acetylcholine receptors

0524282 - FGÚ 2021 RIV GB eng J - Journal Article
Randáková, Alena - Nelic, Dominik - Ungerová, Dana - Nwokoye, P. - Su, Q. - Doležal, Vladimír - El-Fakahany, E. E. - Boulos, J. - Jakubík, Jan
Novel M-2-selective, G(i)-biased agonists of muscarinic acetylcholine receptors.
British Journal of Pharmacology. Roč. 177, č. 9 (2020), s. 2073-2089. ISSN 0007-1188. E-ISSN 1476-5381
R&D Projects: GA ČR(CZ) GA17-16182S
Research Infrastructure: CESNET II - 90042
Institutional support: RVO:67985823
Keywords : muscarinic acetylcholine receptors * functionally selective agonists * signalling bias
OECD category: Physiology (including cytology)
Impact factor: 8.740, year: 2020
Method of publishing: Limited access
https://doi.org/10.1111/bph.14970

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. Two of the tested new compounds 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. 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.
Permanent Link: http://hdl.handle.net/11104/0308655