Title

Optical control of muscular nicotinic channels with azocuroniums, photoswitchable azobenzenes bearing two N-methyl-N-carbocyclic quaternary ammonium groups

Document Type

Article

Publication Title

European Journal of Medicinal Chemistry

ISSN

1768-3254

Volume

200

DOI

10.1016/j.ejmech.2020.112403

First Page

112403

Publication Date

8-15-2020

Abstract

By linking two N-methyl-N-carbocyclic quaternary ammonium groups to an azobenzene scaffold in meta- or para-positions we generated a series of photoswitchable neuromuscular ligands for which we coined the term "azocuroniums". These compounds switched between the (E)- and (Z)-isomers by light irradiation at 400-450 nm and 335-340 nm, respectively. Meta-azocuroniums were potent nicotinic ligands with a clear selectivity for the muscular nAChRs compared to neuronal α7 and α4β2 subtypes, showed good solubility in physiologic media, negligible cell toxicity, and would not reach the CNS. Electrophysiological studies in muscle-type nAChRs expressed in Xenopus laevis oocytes showed that (E)-isomers were more potent than (Z)-forms. All meta-azocuroniums were neuromuscular blockers, with the exception of the pyrrolidine derivative that was an agonist. These new meta-azocuroniums, which can be modulated ad libitum by light, could be employed as photoswitchable muscle relaxants with fewer side effects for surgical interventions and as tools to better understand the pharmacology of muscle-type nAChRs.

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