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  • Title: Hydantoin-substituted 4,6-dichloroindole-2-carboxylic acids as ligands with high affinity for the glycine binding site of the NMDA receptor.
    Author: Jansen M, Potschka H, Brandt C, Löscher W, Dannhardt G.
    Journal: J Med Chem; 2003 Jan 02; 46(1):64-73. PubMed ID: 12502360.
    Abstract:
    A novel series of C-3 substituted 4,6-dichloroindole-2-carboxylic acids was synthesized to investigate the influence of different hydrogen-bond donor and acceptor groups at this specific position on the affinity to the glycine site of the NMDA receptor. These novel 3-indolylmethyl derivatives with ring-open (amines, sulfonamides, amides, ureas) and cyclic substituents (imidazolidin-2-ones, (thio)hydantoins) led to the discovery that compounds bearing a hydantoin substituent at the C-3 position of the indole nucleus are the most promising ones. In this series the hydantoins, ureas, and imidazolidin-2-ones were identified as very potent inhibitors of the binding of the glycine site specific ligand [(3)H]MDL 105,519 to pig cortical brain membranes. Since the hydantoins can be produced via a versatile synthetic approach, further amendments of the hydantoin-substituted compounds were conducted to elucidate the influence of aromatic and aliphatic moieties at position 3 of the hydantoin as well as of sterically hindered compounds (5-substituted hydantoins). On the basis of the pharmacological data obtained in displacement experiments with [(3)H]MDL 105,519 and the emerging structure-activity relationships, we confirm the existing pharmacophore model that suggests a hydrogen-bond acceptor and an aromatic substituent at position 3 of the indole as the key features for high affinity. Log P values indicate brain permeability and selected compounds showed anticonvulsant activity in vivo. Binding studies for the sodium channel (site 2) were also performed on some selected compounds.
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