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.

Conformationally 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 as PowerPoint slide