Y-aminobutyric acid derivatives

Based on the idea that pyrrolidines can be metabolized selectively to y-aminobutyric acid derivatives, Wall and Baker [189] developed a retro-metabolic approach with 3-(4-chlorophenyl)pyrrolidine (5.92, Fig. 5.25) as a prodrug for the GABA-ergic agent baclofen (5.93, Fig. 5.25). In vitro studies showed that metabolism of 5.92 yields a pair of isomeric lactam metabolites (5.94, 5.96) and a pair of isomeric amino acid metabolites (5.93, 5.95). The formation of the metabolites resulting from the oxidation... 

Scheme 4.3. Solid-phase Biginelli condensation using y-aminobutyric acid-derived urea on Wang resin.

More recently, acid hydrolysates have been analysed by HPLC.27 Furosine (see below) was the main product observed for dried figs and apricots, whereas furosine and the y-aminobutyric acid derivative, in about equal amounts, were the main products for prunes and dates. 2-Furoylmethyl-y-aminobutyric acid and -arginine were the most abundant products observed for commercial raisins, ranging from about 10 to 75 mg per 100 g of sample each. Most of the Amadori compounds present in raisins seem to have been formed during storage rather than processing. 

In this sequence, y-aminobutyric acid derived urea 241, prepared from GABA and KOCN in HjO/THF, was attached to Wang resin 84 to provide 242 in high yield. Subsequent... 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

Mechanism of Action The mechanism of action of divalproex is not well understood. It is known to affect ion transport and enhances the activity of y-aminobutyric acid. Like lithium, it also has possible neuroprotective effects through enhancement of brain-derived neurotrophic factor.31... 

A similar pathway involving a microwave-driven molybdenum-catalyzed asymmetric allylic alkylation as the key step was elaborated by Moberg and coworkers for the preparation of the muscle relaxant (R)-baclofen (Scheme 6.52) [108]. The racemic form of baclofen is used as a muscle relaxant (antispasmodic) lipophilic derivative of y-aminobutyric acid (GABA). Pharmacological studies have shown that the (R)-enantiomer is the therapeutically useful agonist of the GABAb receptor. Asymmetric alkylation of the allylic carbonate precursor with dimethyl malonate afforded... 

In earlier studies the in vitro transition metal-catalyzed oxidation of proteins and the interaction of proteins with free radicals have been studied. In 1983, Levine [1] showed that the oxidative inactivation of enzymes and the oxidative modification of proteins resulted in the formation of protein carbonyl derivatives. These derivatives easily react with dinitrophenyl-hydrazine (DNPH) to form protein hydrazones, which were used for the detection of protein carbonyl content. Using this method and spin-trapping with PBN, it has been demonstrated [2,3] that protein oxidation and inactivation of glutamine synthetase (a key enzyme in the regulation of amino acid metabolism and the brain L-glutamate and y-aminobutyric acid levels) were sharply enhanced during ischemia- and reperfusion-induced injury in gerbil brain. 

Wermuth, C. G., Bourguignon, J.-J., Schlewer, G Gies, J.-P., Schoenfelder, A., Melikian, A., et al. (1987) Synthesis and structure-activity relationships of a series of aminopyridazine derivatives of y-aminobutyric acid acting as selective GABA-A antagonists../. Med. Chem. 30, 239-249. 

Larsson, O. M., Falch, E., Krogsgaard-Larsen, P, and Schousboe, A. (1988) Kinetic characterization of inhibition of y-aminobutyric acid uptake into cultured neurons and astrocytes by 4,4-diphenyl-3-butenyl derivatives of nipecotic acid and guvacine. J. Neurochem. 50, 818-823. 

In addition to a-allenic a-amino acids, the corresponding allenic derivatives of y-aminobutyric acid (GABA) have also been synthesized as potential inhibitors of the pyridoxal phosphate-dependent enzyme GABA-aminotransferase (Scheme 18.49) [131,138-142]. The synthesis of y-allenyl-GABA (152) and its methylated derivatives was accomplished through Crabbe reaction [131], aza-Cope rearrangement [138] and lactam allenylation [139], whereas the fluoroallene 153 was prepared by SN2 -reduc-tion of a propargylic chloride [141]. 

Amino acid derivatives include the thyroid hormones, catecholamines (e.g. adrenaline (epinephrine)) and dopamine, neurotransmitters such as y-aminobutyric acid (GABA) and noradrenaline (norepinephrine). All of these signalling molecules retain... 

In contrast to glutamate, y-aminobutyric acid (y-aminobutyrate, GABA) is an inhibitory compound. Metabolically derived from glutamate, GABA production illustrates a reaction, decarboxylation, common to the production of serotonin and the catecholamines (Figure 4.9). 

J. Nakamura, T. Miwa, Y. Mori, H. Saski, Comparative Studies on the Anticonvulsant Activity of Lipophilic Derivatives of y-Aminobutyric Acid and 2-Pyrrolidinone in Mice , J. Pharmacobio-Dynam. 1991, 14, 1-8. 

Biogenic amines arise from amino acids by decarboxylation (see p. 62). This group includes 4-aminobutyrate (y-aminobutyric acid, GABA), which is formed from glutamate and is the most important inhibitory transmitter in the CNS. The catecholamines norepinephrine and epinephrine (see B), serotonin, which is derived from tryptophan, and histamine also belong to the biogenic amine group. All of them additionally act as hormones or mediators (see p. 380). 

An interesting example of biocatalysis and chemical catalysis is the synthesis of a derivative of y-aminobutyric acid (GABA) that is an inhibitor for the treatment of neuropathic pain and epilepsy (Scheme 10.4). The key intermediate is a racemic mixture of cis- and trons-diastereoisomer esters obtained by a hydrogenation following a Horner-Emmons reaction. The enzymatic hydrolysis of both diaste-reoisomers, catalyzed by Candida antarctica lipase type B (CALB), yields the corresponding acid intermediate of the GABA derivative. It is of note that both cis- and trans-diastereoisomers of the desired enantiomer of the acid intermediate can be converted into the final product in the downstream chemistry [10]. 

Zafra F., Castren E., Thoenen H., and Lindholm D. (1991). Interplay between glutamate and y-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc. Natl. Acad. Sci.USA 88 10037-10041. 

Earlier, Sanz et al 6 had found tomato pulp to give a little furosine (7.3 mg per 100 g), with only a trace of 2-l uroylmethyl-y-aminobutyric acid, but, on storage for 4 d at 50 °C and an a, of 0.44, the corresponding amounts were 70.9 and 245.4 mg per 100 g and the amounts for the 2-furoylmethyl derivatives of Ala, Ser + Thr + Glu, and Asp + Asn had come up from 0 to 60.9, 103.5, and 300.5 mg per 100 g, respectively. 2-Furoylmethyl-y-aminobutyric acid was also the most abundant furoyl-methyl derivative obtained from commercial tomato products, ranging from 0 for whole peeled tomatoes to 87.6 mg per 100 g dry matter for double-concentrated tomato paste. Furosine was usually the second most abundant derivative obtained, ranging up to 42.8 mg per 100 g, but its amount exceeded that for 2-furoylmethyl-7-aminobutyric acid in the two samples of tomato pulp analysed. 

Compound (13) and the derivatives (127)—(129) have been useful as a vital stain to serve as a physiological probe for specific neurotransmitter pools. Inhibition of the binding of radiolabeled serotonin, choline, y-aminobutyric acid, noradrenaline, and dopamine was observed <9lMiP9ii4l84>. 

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