1. 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
- Author
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Nancy E. Lee, Donna R. Bramlett, Joanne T. Simmonds, William A. Kinney, Edward J. Podlesny, Dianne Kowal, Deanna T. Garrison, Rene P. Tasse, and Ronald R. Notvest
- Subjects
Male ,Kainic acid ,N-Methylaspartate ,Cyclobutene ,Stereochemistry ,Carboxylic acid ,Carboxylic Acids ,Receptors, N-Methyl-D-Aspartate ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Receptors, Kainic Acid ,Diamine ,Drug Discovery ,Animals ,Quisqualic acid ,Carboxylate ,chemistry.chemical_classification ,Binding Sites ,Chemistry ,Stereoisomerism ,2-Amino-5-phosphonovalerate ,Receptors, Glutamate ,nervous system ,Molecular Medicine ,NMDA receptor ,Bioisostere - Abstract
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.
- Published
- 1992