Novel long‐acting antagonists of muscarinic ACh receptors

0490235 - FGÚ 2019 RIV GB eng J - Journal Article
Randáková, Alena - Rudajev, Vladimír - Doležal, Vladimír - Boulos, J. - Jakubík, Jan
Novel long‐acting antagonists of muscarinic ACh receptors.
British Journal of Pharmacology. Roč. 175, č. 10 (2018), s. 1731-1743. ISSN 0007-1188. E-ISSN 1476-5381
R&D Projects: GA ČR(CZ) GA17-16182S
Institutional support: RVO:67985823
Keywords : muscarinic acetylcholine receptors * long-acting antagonists * tetrahydropyridinium slats
OECD category: Physiology (including cytology)
Impact factor: 6.583, year: 2018

The aim of this study was to develop potent and long-acting antagonists of muscarinic ACh receptors. The 4-hexyloxy and 4-butyloxy derivatives of 1-[2-(4-oxidobenzoyloxy)ethyl]-1,2,3,6-tetrahydropyridin-1-ium were synthesized and tested for biological activity. Antagonists with long-residence time at receptors are therapeutic targets for the treatment of several neurological and psychiatric human diseases. Their long-acting effects allow for reduced daily doses and adverse effects. The binding and antagonism of functional responses to the agonist carbachol mediated by 4-hexyloxy compounds were investigated in CHO cells expressing individual subtypes of muscarinic receptors and compared with 4-butyloxy analogues. The 4-hexyloxy derivatives were found to bind muscarinic receptors with micromolar affinity and antagonized the functional response to carbachol with a potency ranging from 30 nM at M-1 to 4 mu M at M-3 receptors. Under washing conditions to reverse antagonism, the half-life of their antagonistic action ranged from 1.7 h at M-2 to 5h at M-5 receptors. The 4-hexyloxy derivatives were found to be potent long-acting M-1-preferring antagonists. In view of current literature, M-1-selective antagonists may have therapeutic potential for striatal cholinergic dystonia, delaying epileptic seizure after organophosphate intoxication or relieving depression. These compounds may also serve as a tool for research into cognitive deficits.
Permanent Link: http://hdl.handle.net/11104/0284504