Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P80404 (GABA transaminase)
 786 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epilepsy is the most common primary neurological disorder known. In the past decade, various aryl semicarbazones have been designed that were structurally dissimilar from many common anticonvulsants containing the dicarboximide function (CONRCO), which may contribute to toxic side effects. In the present work various N4-(2,6-dimethylphenyl) semicarbazones were designed as pharmacophore hybrids between the aryl semicarbazones and ameltolide. A three-dimensional four-point pharmacophore model was developed for anticonvulsants, and the title compounds were found to match with ralitoline. All of the compounds exhibited anticonvulsant activity in the maximal electroshock test when administered by both intraperitoneal and oral routes. Compound N1-(2,6-dimethylphenyl)-N4-(2-hydroxybenzaldehyde) semicarbazone (9) emerged as a prototype with wide spectrum anticonvulsant agent active in five models of seizure with no neurotoxicity and hepatotoxicity. Compound 9 increased the 4-aminobutyric acid (GABA) level by 118% and inhibited the GABA transaminase enzyme both in vitro and ex vivo.
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PMID:Discovery of N-(2,6-dimethylphenyl)-substituted semicarbazones as anticonvulsants: hybrid pharmacophore-based design. 1619 Jul 47

The biology underlying epileptic brain activity in humans is not well understood and likely depends on changes in gene expression. We performed a microarray transcriptome profiling of 12 anterolateral temporal cortical samples originating from five individuals who suffered with temporal lobe epilepsy for at least 10 years. Prior to partial lobectomy, intraoperative electrocorticography was performed on the cortical surface of each patient. These recordings showed characteristic differences in frequency and amplitude that were defined as "spiking" (abnormal) or "non-spiking" (normal). Between the transcriptome of the two sample groups, transferrin (TF) was the most differentially expressed gene. Furthermore, gene expression profiling also revealed a downregulation of multiple GABA system-related genes (GABRA5, GABRB3, ABAT) in the spiking samples and an upregulation of oligodendrocyte and lipid metabolism transcripts (MOG, CA2, CNP, SCD, PLP1, FA2H, ABCA2). In addition, several transcripts related to the classical MAPK cascade showed expression level alterations between the spiking and non-spiking samples (G3BP2, MAPK1, PRKAR1A, and MAP4K4). Out of 12 genes chosen for verification by RT qPCR, 9 showed significant expression changes in the microarray-predicted direction. Furthermore, the microarray and qPCR data were highly correlated (r = 0.98; P < 0.001). We conclude that abnormal electrical brain activity in the spiking samples is strongly correlated with gene expression changes and we speculate that some of the observed transcriptome changes may be directly involved in the induction or prevention of the ictal events seen in epilepsy.
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PMID:Correlation of transcriptome profile with electrical activity in temporal lobe epilepsy. 1648 Aug 84

Starting from pyrrole, the novel 3,4-didehydropyrohomoglutamate 8 or (ent)-8 can be efficiently synthesized in up to 91% ee, which can be utilized as a versatile building block toward functionalized pyrrolidin-2-ones. Moreover, (ent)-8 can be readily converted to (S)-Vigabatrin, being an irreversible inhibitor for GABA-T, which is used as adjunctive therapy in patients that suffer from epilepsy.
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PMID:Synthesis of functionalized pyrrolidin-2-ones and (S)-Vigabatrin from pyrrole. 1649 13

The use of the antiepileptic drug, 4-aminobutyrate transaminase (GABA-T) inhibitor vigabatrin (VIGA), has been recently cautioned because it is associated to irreversible field defects from damage of the retina. Since novel GABA-T inhibitors might prove useful in epilepsy or other CNS pathologies as VIGA substitutes, the aim of the present investigation was to characterize the biochemical properties of some taurine analogues (TA) previously shown to act as GABA-T inhibitors. These include (+/-)piperidine-3-sulfonic acid (PSA), 2-aminoethylphosphonic acid (AEP), (+/-)2-acetylaminocyclohexane sulfonic acid (ATAHS) and 2-aminobenzenesulfonate (ANSA). Kinetic analysis of the activity of partially purified rabbit brain GABA-T in the presence of VIGA and TA showed that PSA and AEP caused a linear, mixed-type inhibition (Ki values 364 and 1010 microM, respectively), whereas VIGA, ANSA and ATAHS behaved like competitive inhibitors (Ki values 320, 434 and 598 microM, respectively). Among the compounds studied, only VIGA exerted a time-dependent, irreversible inhibition of the enzyme, with Ki and k(inact) values of 773 microM and 0.14 min(-1), respectively. Furthermore, the ability of VIGA and TA to enhance GABA-ergic transmission was assessed in rabbit brain cortical slices by NMR quantitative analysis. The results demonstrate that VIGA as well as all TA promoted a significant increase of GABA content. In conclusion, PSA, ANSA and ATAHS, reversible GABA-T inhibitors with Ki values close to that of VIGA, represent a new class of compounds, susceptible of therapeutic exploitation in many disorders associated with low levels of GABA in brain tissues.
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PMID:Inhibition of rabbit brain 4-aminobutyrate transaminase by some taurine analogues: a kinetic analysis. 1654 97

Lacosamide (LCM) is anticonvulsant in animal models and is in phase 3 assessment for epilepsy and neuropathic pain. Here we seek to identify cellular actions for the new drug and effects on recognised target sites for anticonvulsant drugs. Radioligand binding and electrophysiology were used to study the effects of LCM at well-established mammalian targets for clinical anticonvulsants. 10 microM LCM did not bind with high affinity to a plethora of rodent, guinea pig or human receptor sites including: AMPA; Kainate; NMDA (glycine/PCP/MK801); GABA(A) (muscimol/benzodiazepine); GABA(B); adenosine A1,2,3; alpha1, alpha2; beta1, beta2; M1,2,3,4,5; H1,2,3; CB1,2; D1,2,3,4,5; 5HT1A,1B,2A,2C,3,5A,6,7 and KATP. Weak displacement (25%) was evident at batrachotoxin site 2 on voltage gated Na+ channels. LCM did not inhibit neurotransmitter transport mechanisms for norepinephrine, dopamine, 5-HT or GABA, nor did it inhibit GABA transaminase. LCM at 100 microM produced a significant reduction in the incidence of excitatory postsynaptic currents (EPSC's) and inhibitory postsynaptic currents (IPSC's) in cultured cortical cells and blocked spontaneous action potentials (EC50 61 microM). LCM did not alter resting membrane potential or passive membrane properties following application of voltage ramps between -70 to +20 mV. The voltage-gated sodium channel (VGSC) blocker phenytoin potently blocked sustained repetitive firing (SRF) but, in contrast, 100 microM LCM failed to block SRF. No effect was observed on voltage-clamped Ca2+ channels (T-, L-, N- or P-type). Delayed-rectifier or A-type potassium currents were not modulated by LCM (100 microM). LCM did not mimic the effects of diazepam as an allosteric modulator of GABA(A) receptor currents, nor did it significantly modulate evoked excitatory neurotransmission mediated by NMDA or AMPA receptors (n > or = 5). Evidently LCM perturbs excitability in primary cortical cultures but does not appear to do so via a high-affinity interaction with an acknowledged recognition site on a target for existing antiepileptic drugs.
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PMID:Seeking a mechanism of action for the novel anticonvulsant lacosamide. 1662 Aug 82

Sodium valproate (VPA) has been used clinically for treatment of not only epilepsy but also mood disorder. Although VPA is effective for treatment of epilepsy via inhibition of gamma-aminobutyric acid transaminase, it remains unknown why VPA is effective for the treatment of mood disorder. The authors examined the effect of VPA at therapeutic concentrations (300 and 600 microM) on the elevation of intracellular free calcium concentration ([Ca(2+)](i)) induced by carbachol, a muscarinic receptor agonist, in 1321N1 human astrocytoma cells. Treatment of the cells with 300 and 600 microM VPA for 2 min did not change the carbachol-induced [Ca(2+)](i) elevation. Treatment with 300 and 600 microM VPA for 48 h, however, reduced the elevation. Since we have shown that Li(+) reduced carbachol-induced [Ca(2+)](i) elevation in protein kinase C (PKC)-downregulated 1321N1 cells [Kurita, M., Mashiko, H., Rai, M., Kumasaka, T., Kouno, S., Niwa, S., Nakahata, N., 2002. Lithium chloride at a therapeutic concentration reduces Ca(2+)response in protein kinase C down-regulated human astrocytoma cells, Eur. J. Pharmacol. 442, 17-22.], the activity of PKC was examined. Treatment with VPA at the same concentrations for 24 or 48 h weakly reduced protein kinase C activity in membrane and cytosol fractions from the cells. On the other hand, the treatment of the cells with 600 microM VPA for 24 or 48 h slightly increased the B(max) value, but not the K(d) value, in the binding of [(3)H]quinuclidinyl benzylate, a muscarinic receptor ligand, to the membranes, suggesting that the number or affinity of muscarinic receptor did not decrease after VPA treatment. These results indicate that VPA at therapeutic concentrations slightly decreases the PKC activity and inhibits muscarinic receptor-mediated [Ca(2+)](i) elevation probably through change in the intracellular signaling pathway. VPA-induced reduction of PKC activity and [Ca(2+)](i) elevation may play a role in the treatment of mood disorder.
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PMID:Sodium valproate at therapeutic concentrations changes Ca2+ response accompanied with its weak inhibition of protein kinase C in human astrocytoma cells. 1725 72

Low brain levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) lead to convulsions. Inhibition of GABA aminotransferase increases the concentration of GABA and can terminate the convulsions. Earlier we reported the synthesis of (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid (2), which is 186 times more potent an inactivator of GABA aminotransferase than the epilepsy drug S-vigabatrin. The corresponding dichloromethylene analogue of 2 (compound 3) has been made, but it shows only weak reversible inhibition of GABA aminotransferase. However, the tetrazole isostere of 2 (compound 4) has been found to be a time-dependent inactivator of GABA aminotransferase. Although it is 20 times less potent than carboxylic acid 2, it is 2.5 times more potent than S-vigabatrin. A calculation of the ClogP values indicates that 4 is the most lipophilic of the three, being 69 times more lipophilic than 2 and 55 times more lipophilic than S-vigabatrin, indicating potential for improved bioavailability.
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PMID:Structural modifications of (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid, a potent irreversible inhibitor of GABA aminotransferase. 1726 20

The vitamin B(6)-derived pyridoxal 5'-phosphate (PLP) is the cofactor of enzymes catalyzing a large variety of chemical reactions mainly involved in amino acid metabolism. These enzymes have been divided in five families and fold types on the basis of evolutionary relationships and protein structural organization. Almost 1.5% of all genes in prokaryotes code for PLP-dependent enzymes, whereas the percentage is substantially lower in eukaryotes. Although about 4% of enzyme-catalyzed reactions catalogued by the Enzyme Commission are PLP-dependent, only a few enzymes are targets of approved drugs and about twenty are recognised as potential targets for drugs or herbicides. PLP-dependent enzymes for which there are already commercially available drugs are DOPA decarboxylase (involved in the Parkinson disease), GABA aminotransferase (epilepsy), serine hydroxymethyltransferase (tumors and malaria), ornithine decarboxylase (African sleeping sickness and, potentially, tumors), alanine racemase (antibacterial agents), and human cytosolic branched-chain aminotransferase (pathological states associated to the GABA/glutamate equilibrium concentrations). Within each family or metabolic pathway, the enzymes for which drugs have been already approved for clinical use are discussed first, reporting the enzyme structure, the catalytic mechanism, the mechanism of enzyme inactivation or modulation by substrate-like or transition state-like drugs, and on-going research for increasing specificity and decreasing side-effects. Then, PLP-dependent enzymes that have been recently characterized and proposed as drug targets are reported. Finally, the relevance of recent genomic analysis of PLP-dependent enzymes for the selection of drug targets is discussed.
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PMID:Pyridoxal 5'-phosphate enzymes as targets for therapeutic agents. 1750 14

The effects of vigabatrin, which increases GABA concentrations by inhibiting GABA transaminase, on spike and wave discharges (SWDs) in the electroencephalogram of WAG/Rij rats were studied. Vigabatrin increased the incidence and duration of the SWDs, suggesting a quantitative GABA(A)ergic involvement in the mechanism(s) underlying the starting and stopping of an ongoing SWD. Also, vigabatrin decreased the SWD peak frequency, suggesting an important role of GABA(B) in the mechanism(s) underlying the peak frequency of the SWDs. Vigabatrin gradually changed the course of the hazard rates of the SWD durations, suggesting a qualitative GABAergic role in the mechanism(s) underlying the stopping of an ongoing SWD.
Epilepsy Res 2007 Aug
PMID:The effects of vigabatrin on spike and wave discharges in WAG/Rij rats. 1764 66

GABA is the major inhibitory neurotransmitter in the central nervous system, and its concentration in the brain in associated with a variety of neurological disorders, including seizures, convulsions, and epilepsy. The concentration of GABA is modulated by the pyridoxal-5'-phosphate (PLP)-dependent enzymes, GAD and GABA-T. In this study, we generated pyridoxyl-gamma-aminobutyrate (PL-GABA), a novel GABA analogue composed of pyridoxyl and GABA, and have also characterized its anticonvulsant and pharmacological functions in vitro. The results of biodistribution studies revealed that PL-GABA is capable of crossing the blood-brain barrier. PL-GABA evidenced anticonvulsant activity in a wide range of epilepsy models, some of which were electrically-based (MES seizures) and some chemically-based (bicuculline, pentylenetetrazol (PTZ), picrotoxine, 3-mercaptopropionic acid). Following a timed subcutaneous administration of PTZ to mice, PL-GABA consistently increased the latencies to first twitch and clonus. In addition, PL-GABA displayed no signs of tolerance after subchronic (10 day) treatment. PL-GABA appears to exert its anticonvulsant effects by influencing seizure spread and by raising the seizure threshold. Therefore, our results indicate that PL-GABA exerts a broad-spectrum anticonvulsant effect, and identify the potential for reduced PL-GABA tolerance as an additional positive profile for novel antiepileptic drugs.
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PMID:Anticonvulsant characteristics of pyridoxyl-gamma-aminobutyrate, PL-GABA. 1834 62


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