Novel Non-Competitive Antagonists of Kainate GluK1/GluK2 Receptors

Title:Novel Non-Competitive Antagonists of Kainate GluK1/GluK2 Receptors

Volume: 9 Issue: 10

Author(s): Agnieszka Anna Kaczor, Christiane Kronbach, Klaus Unverferth, Kalevi Pihlaja, Kirsti Wiinamaki, Jari Sinkkonen, Urszula Kijkowska-Murak, Tomasz Wrobel, Tomasz Stachal and Dariusz Matosiuk

Affiliation:

Keywords: Allosteric modulators, Indole derivatives, Glutamate receptors, Kainate receptors, Molecular modelling, Non-competitive antagonists of kainate receptors, ionotropic glutamate receptors, Alzheimer’s disease, NMDA receptor antagonists, Zindoxifene

Abstract: A series of 2,3,5-trisubstituted and 1,2,3,5-tetrasubstituted indoles is synthesized by Fisher or Bischler method, followed by alkylation with an appropriate alkyl or aryl halide. Two compounds exhibit non-competitive antagonism towards GluK1 and six – towards GluK2 receptor. The values of IC50 are in micromolar range. The investigated compounds belong to the most active GluK1 non-competitive inhibitors and are the first known negative allosteric modulators of GluK2 receptor. The observed pattern of activity is rationalized by molecular modelling, in particular by construction of the pharmacophore model.

Cite this article as:

Anna Kaczor Agnieszka, Kronbach Christiane, Unverferth Klaus, Pihlaja Kalevi, Wiinamaki Kirsti, Sinkkonen Jari, Kijkowska-Murak Urszula, Wrobel Tomasz, Stachal Tomasz and Matosiuk Dariusz, Novel Non-Competitive Antagonists of Kainate GluK1/GluK2 Receptors, Letters in Drug Design & Discovery 2012; 9 (10) . https://dx.doi.org/10.2174/1570180811209050891