Bioisosterically modified dipeptide excitatory amino acid receptor antagonists containing 3-oxygenated isothiazole ring systems.
The AMPA receptor agonist Thio-AMPA, the 3-isothiazolol analogue of AMPA was converted into the selective NMDA antagonist, 2, in which a 3-isothiazolone unit is a bioisosteric analogue of the peptide bond of the NMDA antagonist, gamma-(R)-Glu-Gly. The isomeric 3-oxygenated isothiazole amino acid, 3, and the corresponding isothiazole phosphono amino acid 4 were also synthesized, and were shown to be selective AMPA receptor antagonists. Compound 1, in which the peptide bond of gamma-(R)-Glu-Gly is replaced by an ester group, was synthesized and shown to be unstable in the test buffer system.
Matzen
L
L
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Ebert
B
B
Stensbøl
T B
TB
Frølund
B
B
Jaroszewski
J W
JW
Krogsgaard-Larsen
P
P
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003337:Corpus Callosum / Q000187:drug effects / Q000502:physiology; D004151:Dipeptides / Q000378:metabolism*; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D007608:Kainic Acid / Q000378:metabolism; D008956:Models, Chemical; D016202:N-Methylaspartate / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000031:analogs & derivatives* / Q000378:metabolism
D000927:Anticonvulsants; D004151:Dipeptides; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D018091:Receptors, AMPA; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D007608:Kainic Acid