Bioisosteric replacement of the alpha-amino carboxylic acid functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-1,2-dione containing NMDA antagonists. 1992

W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.

In this report, a novel bioisostere of the alpha-amino acid, 3,4-diamino-3-cyclobutene-1,2-dione, has been incorporated into a series of compounds which are NMDA antagonists. These compounds, which are achiral and easily prepared, demonstrated good affinity at the NMDA receptor by their ability to displace [3H]CPP binding in vitro. In particular, the phosphonic acid 24 provided protection against NMDA-induced lethality in mice equivalent to 2-amino-7-phosphonoheptanoic acid (5). This was considered an encouraging result in lieu of the fact that 24, like 5, lacks the conformational rigidity of the more potent NMDA antagonists. In addition, analogs that incorporate the 1,2,4-oxadiazolidine-3,5-dione heterocycle of quisqualic acid and the unsaturation of kainic acid were prepared to explore selectivity at the non-NMDA receptor subtypes.

UI MeSH Term Description Entries
D008297 Male Males
D002264 Carboxylic Acids Organic compounds containing the carboxy group (-COOH). This group of compounds includes amino acids and fatty acids. Carboxylic acids can be saturated, unsaturated, or aromatic. Carboxylic Acid,Acid, Carboxylic,Acids, Carboxylic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015763 2-Amino-5-phosphonovalerate The D-enantiomer is a potent and specific antagonist of NMDA glutamate receptors (RECEPTORS, N-METHYL-D-ASPARTATE). The L form is inactive at NMDA receptors but may affect the AP4 (2-amino-4-phosphonobutyrate; APB) excitatory amino acid receptors. 2-Amino-5-phosphonopentanoic Acid,2-Amino-5-phosphonovaleric Acid,2-APV,2-Amino-5-phosphonopentanoate,5-Phosphononorvaline,d-APV,dl-APV,2 Amino 5 phosphonopentanoate,2 Amino 5 phosphonopentanoic Acid,2 Amino 5 phosphonovalerate,2 Amino 5 phosphonovaleric Acid,5 Phosphononorvaline
D016194 Receptors, N-Methyl-D-Aspartate A class of ionotropic glutamate receptors characterized by affinity for N-methyl-D-aspartate. NMDA receptors have an allosteric binding site for glycine which must be occupied for the channel to open efficiently and a site within the channel itself to which magnesium ions bind in a voltage-dependent manner. The positive voltage dependence of channel conductance and the high permeability of the conducting channel to calcium ions (as well as to monovalent cations) are important in excitotoxicity and neuronal plasticity. N-Methyl-D-Aspartate Receptor,N-Methyl-D-Aspartate Receptors,NMDA Receptor,NMDA Receptor-Ionophore Complex,NMDA Receptors,Receptors, NMDA,N-Methylaspartate Receptors,Receptors, N-Methylaspartate,N Methyl D Aspartate Receptor,N Methyl D Aspartate Receptors,N Methylaspartate Receptors,NMDA Receptor Ionophore Complex,Receptor, N-Methyl-D-Aspartate,Receptor, NMDA,Receptors, N Methyl D Aspartate,Receptors, N Methylaspartate
D016202 N-Methylaspartate An amino acid that, as the D-isomer, is the defining agonist for the NMDA receptor subtype of glutamate receptors (RECEPTORS, NMDA). N-Methyl-D-aspartate,NMDA,N-Methyl-D-aspartic Acid,Acid, N-Methyl-D-aspartic,N Methyl D aspartate,N Methyl D aspartic Acid,N Methylaspartate
D017470 Receptors, Glutamate Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells. Glutamate receptors include ionotropic receptors (AMPA, kainate, and N-methyl-D-aspartate receptors), which directly control ion channels, and metabotropic receptors which act through second messenger systems. Glutamate receptors are the most common mediators of fast excitatory synaptic transmission in the central nervous system. They have also been implicated in the mechanisms of memory and of many diseases. Excitatory Amino Acid Receptors,Glutamate Receptors,Receptors, Excitatory Amino Acid,Excitatory Amino Acid Receptor,Glutamate Receptor,Receptor, Glutamate

Related Publications

W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
March 2008, Bioorganic & medicinal chemistry letters,
W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
October 1995, Journal of medicinal chemistry,
W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
February 2008, Bioorganic & medicinal chemistry letters,
W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
October 1993, Journal of medicinal chemistry,
W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
February 2012, Acta crystallographica. Section E, Structure reports online,
W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
May 2010, Bioorganic & medicinal chemistry,
W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
August 1983, Neuroscience,
W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
August 2006, Bioorganic & medicinal chemistry letters,
W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
January 1991, Journal of medicinal chemistry,
W A Kinney, and N E Lee, and D T Garrison, and E J Podlesny, and J T Simmonds, and D Bramlett, and R R Notvest, and D M Kowal, and R P Tasse
December 1999, Journal of agricultural and food chemistry,
Copied contents to your clipboard!