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.
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.
Kinney
W A
WA
Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Lee
N E
NE
Garrison
D T
DT
Podlesny
E J
EJ
Simmonds
J T
JT
Bramlett
D
D
Notvest
R R
RR
Kowal
D M
DM
Tasse
R P
RP
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D015763:2-Amino-5-phosphonovalerate; D002264:Carboxylic Acids; D016202:N-Methylaspartate; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate