Premium
Novel long‐acting antagonists of muscarinic ACh receptors
Author(s) -
Randáková Alena,
Rudajev Vladimír,
Doležal Vladimír,
Boulos John,
Jakubík Jan
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14187
Subject(s) - muscarinic acetylcholine receptor , carbachol , receptor , chemistry , pharmacology , muscarinic acetylcholine receptor m2 , muscarinic acetylcholine receptor m3 , muscarinic acetylcholine receptor m1 , agonist , antagonism , cholinergic , acetylcholine , neuroscience , biochemistry , biology
Background and Purpose 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. Experimental Approach 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. Key Results 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 μM 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 5 h at M 5 receptors. Conclusions and Implications 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.