During the past 15 years evidence has accumulated implicating the acidic amino acids, glutamic acid and aspartic acid, as excitatory neurotransmitters in the mammalian central nervous system. The N-methyl-D-aspartate (NMDA) receptor complex has attracted considerable interest due to its implication in the etiology of several neurodegenerative disorders and epilepsy, with its strychnine-insensitive glycine binding site facilitating glutamic acid action and requiring potent, selective antagonists for potential use as anticonvulsants or neuroprotective agents. In this communication we report that 3-(4,6-dichloro-2-carboxyindol-3-yl)propionic acid (4f) and other indolepropionic acid derivatives represent a new class of selective NMDA antagonists acting at the strychnine-insensitive glycine binding site. Indoles 4a-f were synthesized via the Japp-Klingemann reaction: hydrazones 2a-f, prepared from 2-(ethoxycarbonyl)cyclopentanone and benzenediazonium salts, were cyclized under Fischer indole reaction conditions to diesters 3a-f, which were saponified to diacids 4a-f. 4,6-Dichloroindole-2-carboxylic acid (5) was also synthesized for comparison. Binding assays showed 4f was a potent antagonist with an IC50 of 0.14 μM against tritiated glycine (strychnine-insensitive site) and 358 μM against tritiated CPP (glutamate site), giving a selectivity ratio (CPP/gly) of 2550. Chlorine substitution at the 4- and 6-positions of the indole ring enhanced potency, while the propionic acid side chain was critical for activity (5, lacking the side chain, was 50-fold less potent than 4f). 4f was also highly selective over kainate (IC50 418 μM) and AMPA (IC50 273 μM) sites. Structure-activity relationships revealed that chlorine at the 4- and 6-positions (but not 5- and 7-) determined antagonist potency, and the propionic acid side chain suggested a secondary receptor pocket. In conclusion, we have discovered a new series of potent antagonists of the strychnine-insensitive glycine binding site associated with the NMDA receptor complex, which should facilitate a more detailed understanding of the pharmacophore for this receptor.