Pharmacological characteristics and binding modes of caracurine V analogues and related compounds at the neuronal alpha7 nicotinic acetylcholine receptor.

Article Details

Citation

Copy to clipboard

Jensen AA, Zlotos DP, Liljefors T

Pharmacological characteristics and binding modes of caracurine V analogues and related compounds at the neuronal alpha7 nicotinic acetylcholine receptor.

J Med Chem. 2007 Sep 20;50(19):4616-29. Epub 2007 Aug 28.

PubMed ID

17722904 [ View in PubMed

]

Abstract

The pharmacological properties of bisquaternary caracurine V, iso-caracurine V, and pyrazino[1,2-a;4,5-a']diindole analogues and of the neuromuscular blocking agents alcuronium and toxiferine I have been characterized at numerous ligand-gated ion channels. Several of the analogues are potent antagonists of the homomeric alpha7 nicotinic acetylcholine receptor (nAChR), displaying nanomolar binding affinities and inhibiting acetylcholine-evoked signaling through the receptor in a competitive manner. In contrast, they do not display activities at heteromeric neuronal nAChRs and only exhibit weak antagonistic activities at the related 5-HT3A serotonin receptor. In a mutagenesis study, five selected analogues have been demonstrated to bind to the orthosteric site of the alpha7 nAChR. The binding site of the compounds overlaps with that of the standard alpha7 antagonist methyllycaconitine, the binding of them being centered in a cation-pi interaction between the quaternary nitrogen atom of the ligand and the Trp149 residue in the receptor, with additional key contributions from other aromatic receptor residues such as Tyr188, Tyr195, and Trp55.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Glycine	Glycine receptor subunit alpha-1	EC 50 (nM)	95499	N/A	N/A	Details