Novel long-acting antagonists of muscarinic ACh receptors

British Journal of Pharmacology
Alena RandákováJan Jakubík

Abstract

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 M1 to 4 μM at M3 receptors. Under washing conditions to reverse antagonism, the half-life of their antagonistic action ranged from 1.7 h at M2 to 5 h at M5 receptors. The 4-hexyloxy derivatives were found to be potent long-acting M1 -preferring antagonists. In view of current literature, M1 -selective antagonists may have therapeutic potenti...Continue Reading

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Citations

May 24, 2019·Neurodegenerative Disease Management·Karlo J LizarragaSusan Fox
Jun 5, 2019·Expert Opinion on Drug Discovery·Sarah Pirio Richardson, H A Jinnah
May 6, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Alena Randáková, Jan Jakubík

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Methods Mentioned

BETA
transfection
saturation binding

Software Mentioned

Libre Office
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