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.
Shou
Xiaohong
X
Department of Chemistry, University of California, Irvine, CA 92697, USA.
Miledi
Ricardo
R
Chamberlin
A Richard
AR
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D015195:Drug Design; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007608:Kainic Acid / Q000031:analogs & derivatives*; D008958:Models, Molecular; D009119:Muscle Contraction; D009865:Oocytes; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014162:Transfection; D014981:Xenopus
D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D017470:Receptors, Glutamate; C057812:indoline; D007608:Kainic Acid