Indole- and indoline-based kainate analogues with antagonist activity at ionotropic glutamate receptors

A conformationally constrained, indole-based kainate analogue was designed based on Gouaux’s X-ray structure of kainic acid bound to an iGluR2(S1S2) construct, a structural model for AMPA/kainate ionotropic glutamate receptors. In contrast to the parent kainic acid, a potent agonist, this compound, along with three structurally related analogues derived from synthetic intermediates, exhibited antagonist behavior towards KAR expressed in oocytes, a result that is rationalized by molecular modeling studies.

Graphical abstractConformationally constrained, indole/indoline-based analogues based on the well-known glutamate receptor agonist kainic acid were designed and synthesized. Screening for ionotropic glutamate receptor activity showed these compounds to be kainate receptor antagonists, rather than agonists.Figure optionsDownload full-size imageDownload as PowerPoint slide