Interaction of Chlorisondamine with the Neuronal Nicotinic Acetylcholine Receptor

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Abstract
An epitope was found on the α2-nicotinic isoform of the neuronal nicotinic acetylcholine receptor that would likely form salt bridges with quaternary ammonium compounds and a cation-π interaction with the π-cloud of an aromatic ring. Chlorisondamine, a nicotinic antagonist, exerts a long-lasting, if not permanent, blockade of the ion channel gated by acetylcholine. Blocking of the ion channel prevents nicotine from exerting its rewarding effect on the CNS. Chlorisondamine contains two quaternary ammonium groups and a tetrachloroisoindoline ring. We propose that chlorisondamine interacts with an epitope on the α2 isoform of the rat neuronal nicotinic receptor (residues 388−402, GEREETEEEEEEEDE), where one or both of the quaternary ammonium groups of chlorisondamine form a salt bridge with either a glutamic acid side chain or a phosphate group, whereas the tetrachlorobenzene portion of the tetrachloroisoindoline ring interacts with the guanidinium group of arginine in a cation-π association. In this work, a new way of probing the interaction of a receptor epitope (α2) with organic molecules (chlorisondamine and hexachlorobenzene) was undertaken using matrix assisted laser desorption/ionization mass spectrometry. Keywords: noncovalent interactions • protein epitopes • quaternary amines • ganglionic blockers