Novel Non-Competitive Antagonists of Kainate GluK1/GluK2 Receptors



: Kaczor AA, Kronbach C, Unverferth K, Pihlaja K, Wiinamaki K, Sinkkonen J, Kijkowska-Murak U, Wrobel T, Stachal T, Matosiuk D

Publisher: BENTHAM SCIENCE PUBL LTD

: 2012

: Letters in Drug Design and Discovery

: LETTERS IN DRUG DESIGN & DISCOVERY

: LETT DRUG DES DISCOV

: 10

: 9

: 10

: 891

: 898

: 8

: 1570-1808


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.



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