AMPA receptors antagonists

The Stille reaction featuring bromoquinoxaline 84 and vinylstannane delivered vinylquinoxaline 85. In addition, 85 was further manipulated to a 5-aminomethylquinoxaline-2,3-dione 86 as an AMPA receptor antagonist [47]. Pd-catalyzed nucleophilic substitution on the benzene ring has also been described [48]. Thus, transformation of 5,8-diiodoquinoxalines to quinoxaline-5,8-dimalononitriles with sodium malononitrile was promoted by PdCl2,(Ph3P)2. 

A-40,926 CSP proved to be suitable for the enantiomeric separation of a selected set of putative AMPA receptor antagonists, having a 2,3-benzodiazepinM-one skeleton and an anticonvulsant activity (Figure 2.22). 

AMPA receptor antagonists acting at the 2,3-benzodiazepine modulatory site seem to have a better safety profile than competitive agents such as NBQX, probably due to their better solubility and associated reduced side-effects such as renal toxicity. It is still not clear for which indications they might be useful, although their effects in animal models of acute and chronic neurodegenerative diseases look quite promising. 

Gitto R, Barreca ML, De Luca L, et al (2004) New trends in the development of AMPA receptor antagonists. Expert Opin Ther Pat 14 1199-1213 Globus MYT, Busto R, Dietrich WD, et al (1988) Effect of ischemia on the in vivo release of striatal dopamine, glutamate, and y-aminobutyric acid studied in intracerebral microdialysis. J Neurochem 51 1455-1464... 

KawasakiYatsugi S, Ichiki C, Yatsugi S, et al (2000) Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model. Neuropharmacology 39 211-217... 

Schielke GP, Kupina NC, Boxer PA, et al (1999) The neuroprotective effect of the novel AMPA receptor antagonist PD 152247 (PNQX) in temporary focal ischemia in the rat. Stroke 30 1472-1477... 

Nishiyama, T., Gyermek, L., Lee, C., Kawasaki-Yatsugi, S., Yamaguchi, T. The spinal antinociceptive effects of a novel competitive AMPA receptor antagonist, YM872, on thermal or formalin-induced pain in rats, Anesth. Analg. 1999, 89, 143-147. 

Fig. 2.5 Structures of kainate and AMPA receptor antagonists. LY382884 (a) and LY382884 diethyl ester (b) are kainate receptor antagonists CP-465022 (c), GYKI 52466 (d) CFM-2 (e) and GYKI 53655 (R= CONHMe) (f) are AMPA receptor antagonists...

AMPA receptor antagonist treatment in ischaemic stroke (Artist-MRI) No No Yes... 

Figure 5.14 Major local descriptor contributions to the MFTA models of activity (a) and selectivity (b) for the AMPA receptor antagonists.

Evolved from a series of iV-phosphonoallsyl-S-aminomethylquinoxaline-2,3-diones (262), AMP397A (66) has emerged. This compound is an orally active, potent competitive AMPA receptor antagonist active in a broad spectrum of anticonvulsant tests. AMP397A combines a... 

Several 2,3-benzodiazepin-4-ones snch as compound GYKI 53 655 (Fignre 16.24) are AMPA receptor antagonists and possess noteworthy anticonvulsant and neuroprotective properties. The corresponding ring-contracted analogs, 6,7-methylene-dioxydihydrophtalazines (componnd SYM 2207) and 6,7-methylene-dioxyphtalazin-l(27/)-ones, possess a similar activity profile (compound 17)." " ... 

FIGURE 16.38 The conjunctive method applied to the design of NMDA and AMPA receptor antagonists. 

Ornstein, P. L., Arnold, M. B., Augenstein, N. K., Lodge, D., Leander, J. D., Schoepp, D. D. (3SR,4aRS,6RS,8aRS)-6-[2-(li7-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid a structurally novel, systematically active, competitive AMPA receptor antagonist. J. Med. Chem. 1993, 36, 2046-2048. 

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