Josef A. Schneider

Chapter 4 Excitatory Amino Acids and Mammalian CNS Function

Publisher Summary The research in understanding the importance of excitatory amino acids (EAAs) as potential neurotransmitters has been slow, in part, because glutamate (GLU) and aspartate (ASP) play key metabolic roles in both neuronal and nonneuronal tissues. GLU and ASP exist in high concentrations in the brain tissue (from 1–10 mM intracellularly and 10–100 pM extracellularly) with small differences in levels between the brain regions. There is also a possibility that other dibasic acids are the actual neurotransmitters that activate EAA receptors (rather than GLU and ASP). By reducing the actions of excitatory neurotransmission processes in the central nervous system (CNS), EAA antagonists may have actions similar to those of agonists or facilitators of the inhibitory amino acid neurotransmission— that is, gamma-aminobutyric acid (GABA)-mimetics, GABA-transaminase inhibitors, and benzodiazepines. The concept that n -methyl- d -aspartate (NMDA) receptor antagonists are equivalent to GABA receptor modulators (that is, the benzodiazepines) has been validated with available compounds despite their intrinsic limitations. It may be noted, however, that chemical efforts in the EAA area have been somewhat sparse and that increased efforts to discover more novel structures may provide entities that are more specific in their actions and are devoid of some of the problematic side effects. Such compounds would have promise as novel anxiolytics and anti-convulsants in addition to their anti-neurodegenerative properties. These may allow efforts in this area to extend beyond the NMDA receptor based on the more recent findings related to the multiplicity of EAA receptor-interactions with associated ion channels.

Synthesis and Polymerization of Carbamate-Linked Cyclodextrin Methacrylate Monomers

Abstract A one-step synthesis for cyclodextrin methacrylate monomers was examined starting from α-, β- and γ-cyclodextrin. The reaction of 2-isocyanatoethyl methacrylate as well as allylisocyanate with the corresponding cyclodextrin gave the monofunctionalized carbamate-linked cyclodextrin methacrylates 2, 6 and 9 and allylcarbamates 11 and 14 in moderate yields. By NMR spectroscopic means, it could be proven that in all cases only the primary 6-hydroxyl groups of the cyclodextrins reacted with the isocyanate group. For the synthesis of a β-cyclodextrin monoallyl compound, a substitution reaction of purchasable 6-O-monotoluenesulfonyl-β-cyclodextrin with allylamine gave 6-N-allylamino-6-deoxy-β-cyclodextrin 18 in high yield. The reaction of 2-isocyanatoethyl methacrylate with α-cyclodextrin to the 6-O-carbamoyl-2-methylpropenoylethyl-α-cyclodextrin (2) was optimized so that the monomer 2 could be prepared on a larger scale without chromatographic separation. The aqueous radical homopolymerization of 2 wit...

Chapter 2. Anticonvulsant Agents

Publisher Summary This chapter discusses the present researches regarding the anti-convulsant agents. A need exists for improved anti-convulsant drugs as currently marketed anti-convulsants are associated with a wide range of side effects. New biological models offer alternatives to traditional screens, such as electroshock- and pentylenetetrazol (PTZ)-induced seizures, and portend significant progress in delineating the mechanism(s) of the epilepsies. Genetic animal models of epilepsy are increasingly used for anti-convulsant screening. Among the new mechanistic approaches, the most novel is that of the excitatory amino acid antagonists. Three classes of excitatory amino acid receptors, named after their most potent known agonists, are recognized: N-methyl-D-aspartate (NMDA), α-kainate, and quisqualate-glutamate receptors. 7-Phosphono-2-aminoheptanoic acid (AP7, 1a) and 5-phosphono-2-aminopentanoic acid (AP5, 1b) are claimed to be potent, selective antagonists at NMDA receptors. The decrease in brain aspartate levels induced by valproic acid (VPA) and several anticonvulsant analogs correlates well with anti-convulsant potency; surprisingly, elevations of gamma-aminobutyric acid (GABA) levels do not correlate as well. Inhibitory amino acids, particularly GABA, continue to be a rewarding mechanistic target for the development of novel anti-convulsants. Notably, the enhancement of GABAergic neurotransmission can be accomplished by several means and may enhance the inhibition of seizures. Glycine potentiates the anti-convulsant effects of the GABA agonist musimol and the GABA-transaminase inhibitor γ-vinyl GABA. The anti-convulsant profile of taurine has been extended to include penicillin-induced focal epilepsy. The complex relationships between opioids and epileptogenic activity continue to generate controversy. Anti-convulsant actions of opiates and opiate-related proconvulsant activity may occur at overlapping the drug doses. Comparison of the anti-convulsant activity of phenytoin shows potency to increase the order of phenytoin and its analogues suggesting that hydrogen bonding is important for anti-convulsant activity.