Glutamate synthase inhibitors

Attention then turned to the mechanism of glutamate-induced neurotoxicity in the brain. Evidence was provided that NO mediates glutamate neurotoxicity in primary cortical cultures (Dawson et ai, 1991). NO synthase inhibitors and hemoglobin prevented NMDA- and glutamate-induced neurotoxicity on the other hand, L-arginine reversed the effect of NO synthase inhibitors, and sodium nitroprusside (which decomposes to NO) caused neurotoxicity that paralleled cyclic GMP formation. In the cerebral cortex, NO synthase immunoreactivity was found to be confined to a discrete population of aspiny neurons comprising... 

NO has been implicated in mediating the release of neurotransmitter/neuro-modulators such as substance P or glutamate (Meller and Gebhart, 1993). In addition, glial activation and cytokine production are found to be induced by NO (Guo et al., 2007 Holguin et al., 2004). The role of NO in activated astrocyte-induced glial cytokines after i.t. injection of M3G was examined by using the NO synthase inhibitor L-NAME. In mice treated with M3G, L-NAME was also very... 

The best-known inhibitors are glufosinate and methionine sulfoximine (MSO). Bilanafos, trialaphos, and phosalacine are substances produced by various Streptomyces and other bacteria. They are not inhibitory to glutamate synthase as such, but are hydrolyzed to phosphinotricin (PPT). Glufosinate is the synthetic variant of PPT and is a mixture of the D and L forms. Note that these substances have direct bonds between phosphorus and carbon, which is seldom found in natural compounds. 

Fig. 26.18 Structure-based design of thymidylate synthase inhibitors, (a) Drug lead 2-methyl-2-desamino-/ / °-propargyl-5,8-dideazafolic acid, (b) Derivative lacking the CO-L-glutamate mpiety. (c) Designed diphenylsulfone derivative, (d) AG85, a designed A7-sulfonylindole derivative selected for clinical evaluation.

Inhibitor studies (Leaet al., 1979) have shown that the synthesis of protein from glutamine by isolated pea cotyledons is unaffected by MSO but inhibited by azaserine, consistent with the action of glutamate synthase but not very conclusive because of the side effects of azaserine. Little if any labeling data on ammonia assimilation has so far been produced using developing seeds. 

However, models which assume that ammonia is assimilated solely via GDH cannot account in quantitative terms for the observed rates of NH/ incorporation (Rhodes et al, 1980 Fentem et ai, 1983a). Rhodes et ai, (1989) modeled the kinetics of NH4 incorporation in tobacco cell cultures and suggest that up to 30% of the ammonia assimilated may enter via the GDH reaction. However, the relative sizes of the glutamate and glutamine pools made it difficult to distinguish between the simultaneous operation of alternative pathways and Rhodes et al. were unable to verify the model when inhibitors of GS and GOGAT were used to block the glutamate synthase cycle. 

Both threo- (14) and eo f >"4-fluoro-DL-glutamic acid (/5) are noncompetitive inhibitors of glutamine synthase, an enzyme that catalyzes the synthesis of glutamine from L-glutamic acid and ammonia. This mhibibon may explain the... 

Opioids also interact with excitatory amino acid neurotransmitters. At lower micromolar concentrations, p agonists (e.g., DAMGO) enhance NMDA activity in the nucleus accumbens, but inhibit non-NMDA activity (Martin et al. 1997). At higher concentrations (5 pM), NMDA currents are reduced. Conversely, central administration of glutamate can precipitate a withdrawal syndrome in morphine-dependent animals, similar to the opioid antagonist naloxone. NMDA mechanisms also appear to be involved in the development of morphine tolerance. Competitive and noncompetitive NMDA antagonists and inhibitors of nitric oxide synthase reduce or eliminate tolerance to morphine (Elliott et al. 1995 Bilsky et al. 1996). However, this does not occur for tolerance to k opioids. Pharmacokinetics... 

Among the numerous enzymes that utilize pyridoxal phosphate (PLP) as cofactor, the amino acid racemases, amino acid decarboxylases (e.g., aromatic amino acids, ornithine, glutamic acid), aminotransferases (y-aminobutyrate transaminase), and a-oxamine synthases, have been the main targets in the search for fluorinated mechanism-based inhibitors. Pharmaceutical companies have played a very active role in this promising research (control of the metabolism of amino acids and neuroamines is very important at the physiological level). 

ZD-9331 is a non-nucleosidic inhibitor of thymidylate synthase. It is also an antifolate, in which the quinazoline moiety replaces the pteridine entity, structurally close to methylene tetrahydrofolate (i.e., the second substrate of thymidylate synthase). Moreover, replacement of the acid function of glutamic acid by a tetrazole renders polyglutamination impossible. Consequently, ZD-9331 is active on tumors that are resistant to the usual antifolates. ... 

The mode of action of sulfanilamides became known around 1947, when the structure and biosynthesis of folic acid were elucidated. This compound is built by bacteria from the heterocyclic pteroyl moiety, p-aminobenzoate, and glutamate. p-Aminobenzene-sulfonamide (9.89, sulfanilamide) is a competitive inhibitor of the synthase enzyme, acting as an antimetabolite of p-aminobenzoate. Occasionally, the sulfanilamide can even be incorporated into the modified folate, resulting in an inactive compound and thus an inactive enzyme. This theory, proposed by Woods and Fildes in 1940, became the first molecular explanation of drug action. 

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