Exploration of phenyl-spaced 2-amino-(5-9)-phosphonoalkanoic acids as competitive N-methyl-D-aspartic acid antagonists

To investigate the preferred spatial relationship of the distal phosphonic acid to the alpha-amino acid group of the established competitive N-methyl-D-aspartic acid (NMDA) antagonists APH (1) and APV (2), we have prepared a series of ortho-, meta-, and para-substituted (phosphonoalkyl)phenylglycine...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1989-07, Vol.32 (7), p.1580-1590
Main Authors: Bigge, Christopher F, Drummond, James T, Johnson, Graham, Malone, Thomas, Probert, Albert W, Marcoux, Frank W, Coughenour, Linda L, Brahce, Laura J
Format: Article
Language:English
Subjects:
Amino Acids - pharmacology
Animals
Aspartic Acid - analogs & derivatives
Aspartic Acid - antagonists & inhibitors
Chemical Phenomena
Chemistry
Exact sciences and technology
Male
Mice
N-Methylaspartate
Noncondensed benzenic compounds
Organic chemistry
Organophosphorus Compounds - pharmacology
Preparations and properties
Rats
Rats, Inbred Strains
Receptors, N-Methyl-D-Aspartate
Receptors, Neurotransmitter - metabolism
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Summary:To investigate the preferred spatial relationship of the distal phosphonic acid to the alpha-amino acid group of the established competitive N-methyl-D-aspartic acid (NMDA) antagonists APH (1) and APV (2), we have prepared a series of ortho-, meta-, and para-substituted (phosphonoalkyl)phenylglycine and -phenylalanine derivatives. With use of a [3H]CPP receptor binding assay, significant binding activity was observed to be critically dependent on both the position of substitution and length of alkyl spacing groups. Two compounds, 4-(phosphonomethyl)-phenylglycine (6, PD 129635) and 3-(phosphonomethyl)phenylalanine (15, PD 130527), displayed receptor-binding affinity comparable to that of APH. Like APH, these compounds were also effective in antagonizing both the proconvulsant and lethal action of NMDA-administered retrobulbar in the mouse. Data are also provided which compare directly the binding efficacy of these compounds against that disclosed recently for the related NMDA antagonist 18 (NPC 451). A preliminary comparison of the structures showing good receptor-binding affinity and in vivo antagonist activity suggests that the NMDA receptor prefers a "folded" rather than "extended" conformation.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00127a030