5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition

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Abstract

NMDA antagonists derived from 5-phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione (3a) are potent anticonvulsant agents, and display strong protective effects in the electroshock-induced convulsion assay in mice. Their preference for the human NMDAR 1A/2A over 1A/2B subunit composition was optimized, leading to (1RS,1′S)-PEAQX (9r), which shows a >100-fold selectivity.

NMDA antagonists derived from 5-phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione are potent anticonvulsant agents. Their preference for the human NMDAR 1A/2A over 1A/2B subunit composition was optimized, leading to (1RS,1′S)-PEAQX, which shows a >100-fold selectivity.

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Chemistry

α-Unsubstituted 5-phosphonomethylquinoxalinediones were obtained from 5-bromomethylquinoxalines, for example 13a (Scheme 1), which reacted with trimethylphosphite to yield dimethyl phosphonate 2, and after acidic hydrolysis 5-phosphonomethylquinoxalinedione 3d. Alternatively, hydrogenolysis or replacement of the bromine atom in a Suzuki reaction yielded, after hydrolysis, Figure 1, Scheme 1 or 3e. The 7-chloro and 7-fluoro analogues (3b and 3c) were prepared from the corresponding

Biological Activity

The parent structure, 5-phosphonomethylquinoxaline-dione (Figure 1, Scheme 1), is a highly potent antagonist with subnanomolar affinity in the [3H]CGP39653 binding assay6a for NMDA receptors. In vivo, it shows a very long duration of action, with an ED50 value in the mouse electroshock-induced seizure test (MES)7 of 1.1 mg/kg, 8 h after ip administration, and 6.7 mg/kg, 8 h after oral administration. Variation of the aromatic substitution on C(7) (3be) shows that this position is largely

Acknowledgements

The authors would like to thank C. Boesch, R. Boesch and P. Schmid for skillful synthetic support. Thanks also to P. Martin and N. Reymann for running the radioligand binding assays, to C. Portet and A. Jeker for the anticonvulsion tests, and to R. Brom for the oocyte work.

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Present address: Firmenich SA, CP 239, rte des Jeunes 1, 1211 Geneve 8, Switzerland.

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