Hydantoin-substituted 4,6-dichloroindole-2-carboxylic acids as ligands with high affinity for the glycine binding site of the NMDA receptor.
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.
Jansen
Michaela
M
Institut für Pharmazie, Johannes Gutenberg-Universität, D-55099 Mainz, Germany.
Potschka
Heidrun
H
Brandt
Claudia
C
Löscher
Wolfgang
W
Dannhardt
Gerd
G
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D004597:Electroshock; D005260:Female; D005998:Glycine / Q000378:metabolism*; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D013329:Structure-Activity Relationship; D013552:Swine
D000927:Anticonvulsants; D006827:Hydantoins; D007211:Indoles; D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine