Anti-convulsant activity

N-Alkylamino carbazoles (e.g., 494 and 495) possess significant anti-convulsant and diuretic activity. Introduction of an aminopropyl chain at the N-atom seems to enhance the anti-convulsant activity in combination with methoxy groups at positions 2, 3, and 4, or a chlorine atom at the C-2 and C-3 positions (458). 

Anti-convulsant activity. Methanol (50%) extract of the dried leaf, administered to mice, was active vs leptazol-induced convulsions . Ethanol (70%) extract of the fresh leaf, administered intraperito-neally to mice of both sexes at variable doses, was active vs metrazole- and strychnine-induced convulsions . Anti-estrogenic effect. Aqueous extract of the dried leaf smoke, administered to female adults at a concentration of 25.0 pL/plate, was active on granulosa cells. Results significant atp < 0.001 level . 

Montanine alkaloids are members of the alkaloids of the plant family of Amarylli-daceae. They represent a relatively small class of compounds with the typical methanomorphanthridine skeleton exhibiting some anxiolytic, anti-depressive and anti-convulsive activities [135, 136]. The total syntheses of the natural (-)-mon-tanine enantiomers are only mentioned, not described, here (for these (—(-enantiomers see, e.g. literature cited in [137]). 

With the PTZ procedure, pro- or anti-convulsant activity is indicated both by the frequency of the convulsant events (clonic convulsions, tonic convulsions, deaths) and by their latency of occurrence. Latency is the measure which most clearly identifies pro-convulsant activity, whereas frequency is the measure most useful for detecting anticonvulsant activity. A statistical problem arises when the test substance completely blocks convulsions in some of the animals. 

With the PTZ procedure described above, using 120 mg/kg PTZ, convulsions are observed in 100% of the animals. Variants exist whereby lower doses of PTZ, for example 60 mg/kg, are administered with the aim of rendering the test more sensitive to proconvulsant effects. The problem with this approach is that convulsions are not observed in 100 % of the animals, thereby weakening the possibilities for a sensitive statistical analysis. When 100 % of the control animals convulse after PTZ, the latency measures become the indices of choice for demonstrating pro-or anti-convulsant activity. 

As mentioned, GABA is an important neural transmitter and deficiencies in GABA are associated with diseases that exhibit neuromuscular dysfunction such as epilepsy, Huntington s disease and Parkinson s disease. S-Aminopentanoic acid (S-aminovaleric acid, DAVA) is also a neurotransmitter and used for treatment of neuromuscular disease. In at least one study, 3-alkyl-4-aminobutanoic acid derivatives were shown to be in vitro activators of f glutamic acid decarboxylase and they showed anti-convulsant activity. ... 

Fig. 3). Surprisingly, it was shown that the plasma levels of the metabolite were approximately 700 times those of the parent drug. Since the effectiveness of these two compounds is equivalent this result strongly implicates the metabolite as responsible for the anti-convulsant activity. 

Substituted thieno[2,3-iflpyrimidines are considered to be an universal molecules in a structure-based drug design [119], Thieno[2,3-r pyrimidine derivatives show pronotmced anti-inflammatory [120], anti-tumor [121], radioprotective and anti-convulsing activity [122], The pharmacological versatility of the above system also present in substanees with depressant or sedative properties [123] and compoimds used for therapy of malaria [124], tuberculosis [125], Parkinson s disease [126] and other diseases were designed [127],... 

Many patents have been issued on the use of pyrogaUol derivatives as pharmaceuticals. PyrogaUol has been used extemaUy in the form of an ointment or a solution in the treatment of skin diseases, eg, psoriasis, ringworm, and lupus erythematosus. GaUamine triethiodide (16) is an important muscle relaxant in surgery it also is used in convulsive-shock therapy. Trimethoprim (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is an antimicrobial and is a component of Bactrin and Septra. Trimetazidine (l(2,3,4-trimethoxybenzyl)piperazine (Vastarel, Yosimilon) is used as a coronary vasodilator. l,2,3,4-Tetrahydro-6-methoxy-l-(3,4,5-trimethoxyphenyl)-9JT-pyrido[3,4- ]indole hydrochloride is useful as a tranquilizer (52) (see Hypnotics, sedatives, ANTICONVULSANTS, AND ANXIOLYTICS). Substituted indanones made from pyrogaUol trimethyl ether depress the central nervous system (CNS) (53). Tyrosine-and glycine(2,3,4-trihydroxybenzyl)hydrazides are characterized by antidepressant and anti-Parkinson activity (54). 

Kent, AP and Webster, RA (1983) The evaluation of different types of anti-convulsant drug activity against leptazol-induced epileptogenic activity in the anaesthetised rat. Brit. J. Pharmac. 78 553-559. 

This peripheral activity may be a rational basis for the use of systemic local anaesthetics in neuropathic states since ectopic activity in damaged nerves has been shown to be highly sensitive to systemic sodium channel blockers. This too is probably part of the basis for the analgesic effects of established effective anti-convulsants that block sodium channels such as carbamazepine, although central actions are important and may even predominate. The precise actions of excitability blockers therefore remains hazy as does any clear basis for the effectiveness of antidepressants and other adrenergic agents in the treatment of neuropathic pain as both central and peripheral actions, including sympathetic effects are possible. 

Tatulian, L., Delmas, P., Abogadie, F. C., Brown, D. A. Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine, The Journal of Neuroscience 2001, 21, 5535-5545. 

Wickenden, A. D., Yu, W., Zou, A., Jegla, T., Wagoner, P. K. Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels, Molecular Pharmacology 2000, 58, 591-600. 

Two different chiral auxiliary approaches have been applied to the synthesis of NPS 1407 and it s enantiomer (119) (147). NPS 1407 is an antagonist of the glutamate NMDA receptor that has in vivo activity in neuroprotection and anti-convulsant assays. The J2-en-antiomer was synthesized in four steps from (116)with the chiral center introduced by. a completely stereoselective alkylation of hydra-zone (117). The chiral auxiliary, jS-( )-l-ami-no-2-(methoxylmethyl)pyrrolidine (SAMP), was introduced by condensation with aldehyde (116) and removed by catalytic hydro-genolysis. In the second method, the S-enan-tiomer was formed in a four-step sequence with the chiral center installed by the Michael addition of chiral amine (121) (formed in one step from the readily available a-methylben-zylamine) to benzyl crotonate (120). NPS 1407 (123) was found to be 12 times more potent than it s enantiomer (119)at the NMDA receptor in an in vitro assay. 

Introduction During 1966, several new types of chemical structures were reported to have central nervous system depressant activity, and further studies were described of compounds previously classified in this area. The problem of defining further the type of activity to predict whether a given depressant will be of clinical application as an antipsychotic, anti-anxiety agent, sedative, hypnotic, anti-convulsant or anesthetic continues to occupy the attention of many investigators. 

Certain 4-thiazolin derivatives (483) show significant activity as anti-convulsant agents <94FES133>. Thiazolo[3,4-a]benzimidazoies (484) show reproducible in vitro anti-HIV activity <91FES817,91FES925). The enantiomeric resolution of these compounds is achieved by HPLC on a chiral stationary phase <94Mi 306-04>. 

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