3-Quinuclidinyl-α-methoxydiphenylacetate: A multi-targeted ligand with antimuscarinic and antinicotinic effects designed for the treatment of anticholinesterase poisoning.

Autor: Timperley CM; Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK. Electronic address: cmtimperley@dstl.gov.uk., Bird M; Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK., Gore SJ; Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK., Lindsay CD; Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK., Rice H; Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK., Tattersall JEH; Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK., Whitmore CL; Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK., Green AC; Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Jazyk: angličtina
Zdroj: Toxicology letters [Toxicol Lett] 2020 Jun 01; Vol. 325, pp. 67-76. Date of Electronic Publication: 2020 Feb 01.
DOI: 10.1016/j.toxlet.2020.01.027
Abstrakt: Racemic 3-quinuclidinyl-α-methoxydiphenylacetate (MB266) was synthesised. Its activity at muscarinic acetylcholine receptors (mAChRs), and muscle and neuronal nicotinic acetylcholine receptors (nAChRs), was compared to that of atropine and racemic 3-quinucidinyl benzilate (QNB) using a functional assay based on agonist-induced elevation of intracellular calcium ion concentration in CN21, Chinese Hamster Ovary (CHO) and SHSY5Y human cell lines. MB266 acted as an antagonist at acetylcholine receptors, displaying 18-fold selectivity for mAChR versus nAChR (compared to the 15,200-fold selectivity observed for QNB). Thus O-methylation of QNB reduced the affinity for mAChR antagonism and increased the relative potency at both muscle and neuronal nAChRs. Despite MB266 having a pharmacological profile potentially useful for the treatment of anticholinesterase poisoning, its administration did not improve the neuromuscular function in a soman-poisoned guinea-pig diaphragm preparation pretreated with the organophosphorus nerve agent soman. Consideration should be given to exploring the potential of MB266 for possible anticonvulsant action in vitro as part of a multi-targeted ligand approach.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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