6-(4-Pyridinyl)-1H-1,2,3-triazolo[4,5-d]-pyrimidin-4(5H)-one: A Structurally Novel Competitive AMPA Receptor Antagonist

• Published in: Journal of medicinal chemistry Vol. 38; no. 4; pp. 587 - 589
• Main Authors: Subramanyam, Chakrapani, Ault, Brian, Sawutz, David, Bacon, Edward R, Singh, Baldev, Pennock, Patrick O, Kelly, Michael D, Kraynak, Matthew, Krafte, Doug, Treasurywala, Adi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.02.1995; Amer Chemical Soc
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism; Biological and medical sciences; Chemistry, Medicinal; Glutamatergic system (aspartate and other excitatory aminoacids); Hippocampus - drug effects; Hippocampus - metabolism; Humans; Life Sciences & Biomedicine; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Receptors, AMPA - antagonists & inhibitors; Science & Technology; Triazoles - chemistry; Triazoles - pharmacology; AMINO-ACID RECEPTORS; CONVENIENT; GLUTAMATE; PHARMACOLOGY; DAMAGE; Vertebrata; AMPA receptor; Structure activity relation; Frog; Animal; Amphibia; Salientia; Glutamate receptor; Antagonist; In vitro; Pyridine derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00004a003

The excitotoxic effects of the endogenous neurotransmitter glutamate are widely believed to be a major causative factor in the etiology of stroke and cerebral ischemia. Also, there is considerable circumstantial evidence that implicates excessive stimulation of glutamate receptors in triggering neuronal degradation in other neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). Due to the pioneering efforts of molecular biologists and pharmacologists, three major ionotropic glutamate receptor subtypes have been identified. These ionotropic receptors are named for the agonists that activate them: N-methyl-D-aspartic acid (NMDA), 2-amino-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA), and kainic acid (KA). These receptor subtypes offer a potential for intervention in the discovery of novel therapeutic agents for the treatment of various neurodegenerative diseases. The recent discovery that NBQX (1) and DNQX (2), which are selective and potent AMPA receptor antagonists, are neuroprotective in various animal models of global and focal ischemia has attracted considerable interest in the identification of other classes of AMPA antagonists. Herein, we report that 6-(4-pyridinyl)-1H-1,2,3-triazolo [4,5-d]pyrimidin-4(5H)-one (3) is a potent competitive antagonist of the AMPA subtype glutamate receptor.