Anticonvulsive agent

There ate many classes of anticonvulsant agent in use, many associated with side effect HabiUties of unknown etiology. Despite many years of clinical use, the mechanism of action of many anticonvulsant dmgs, with the exception of the BZs, remains unclear and may reflect multiple effects on different systems, the summation of which results in the anticonvulsant activity. The pharmacophore stmctures involved are diverse and as of this writing there is htde evidence for a common mechanism of action. Some consensus is evolving, however, in regard to effects on sodium and potassium channels (16) to reduce CNS excitation owing to convulsive episodes. 

Another class of therapeutic agents is used for the treatment of certain genetic diseases or other enzymatic disorders caused by the dysfunction or absence of one particular enzyme. This often leads to an unwanted accumulation or imbalance of metaboUtes in the organism. Eor example, some anticonvulsive agents are inhibitors for y-aminobutyric acid aminotransferase [9037-67-6]. An imbalance of two neurotransmitters, glutamate and y-aminobutyric acid, is responsible for the symptoms. Inhibition of the enzyme leads to an increase of its substrate y-aminobutyric acid, decreasing the imbalance and subsequently relieving the symptoms of the disease. 

The synthesis of l-phenyl-2-(phenylcarbamoyl)pyrazolidines (721) afforded a new series of anticonvulsant agents (79JPS377). 

The activity of acylureas as hypnotic and anticonvulsant agents is dealt with in some detail later. This is again one of the cases in which the functionality rather than structure determines pharmacologic activity. Thus, acylation of urea with phenylacetyl chloride gives the anticonvulsant agent, phenacemide... 

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

The close structural resemblance between the sedative-hypnotic and anticonvulsant agents was mentioned earlier. It is interesting that the two activities can be related in at least one case by a simple chemical transformation. Thus, reductive desulfurization of the thiobarbituric acid, 158, affords primi-... 

Reaction of 2,3-dichlorobenzoyl chloride with cyanide ion leads to the corresponding benzoyl cyanide (141). Condensation of that reactive intermediate with aminoguanidine 142 leads to the hydrazone-like product 143. Treatment with base results in addition of one of the guanidine amino groups to the nitrile function and formation of the 1,2,4-triazine ring. The product, lamo-trigine (144), is described as an anticonvulsant agent [31]. 

Hydantoins are well-known anticonvulsant agents and as such have found extensive use in the treatment of epilepsy. Replacement of one of the carbonyl groups by thiocarbonyl is consistent with anticonvulsant activity. Thus, condensation of the ethyl ester... 

Knutsen, L. J., Andersen, K. E., Lau, J., et al. (1999) Synthesis of novel GABA uptake inhibitors. 3. Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents. J. Med. Chem. 42, 3447-3462. 

Meldrum, B. S., Croucher, M. J., and Krogsgaard-Larsen, P. (1981) GABA-uptake inhibitors as anticonvulsant agents, in Problems in GABA Research From Brain to Bacteria (Okada, Y. and Roberts, E., eds.) Excerpta Medica, Amsterdam, pp. 182-191. 

From extensive studies in the field of pharmacologically active pyridazines performed in France, interesting novel anticonvulsant agents emerged. Out of a series of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines prepared [169, 184], compounds CM 40907 (CAS 93181-81-8) (54, R = H) and SR 41378 (CAS 93181-85-2) (55, R = Cl) appear to be of particular interest. 

The anticonvulsant agent primidone (4.246) is the 2-dihydro derivative of phenobarbital (4.247), which is one of its metabolites. The second major metabolite, 2-ethyl-2-phenylmalondiamide (4.248), is produced by a double C-N cleavage [160]. The profile of plasma levels in rats strongly suggests that 2-ethyl-2-phenylmalondiamide is not derived from the metabolite phenobarbital, but directly from primidone. Indeed, a C(2)-hydroxylated metabolite serves as an intermediate for both detected metabolites (see also Chapt. 6 in [21]). N-Alkyl derivatives of primidone yield a greater proportion of ring-opened metabolites, an observation explained by their higher susceptibility to oxidative metabolism at C(2) [161]. 

S. W. Martin, F. E. Bishop, B. M. Kerr, M. Moor, M. Moore, P. Sheffels, M. Rashed, J. G. Slatter, L. Berthon-Cedille, F. Lepage, J.-J. Descombe, M. Picard, T. A. Baillie, R. H. Levy, Pharmacokinetics and Metabolism of the Novel Anticonvulsant Agent N-(2,6-Dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) in Rats and Humans , Drug Metab. Dispos. 1997, 25, 40-46. 

Experimental Validation I As a result of computational screening of the NCI database, 27 compounds were selected as potential anticonvulsant agents and submitted to our experimental collaborators. Of these 27 compounds, our collaborators selected two... 

Experimental Validation 11 Mining of the Maybridge database yielded two compounds that were synthesized and sent to NIH for the MBS anticonvulsant test. Very promising and exciting results have also been obtained. One of the compounds (C9) shows moderate anticonvulsant activity of ED50 between 30 and 100 mg kg (in mice), while the other (C8) is a very potent anticonvulsant agent with ED50 of 18 mg kg" in mice (ip). In summary, both compounds were found to be very active in both mice and rats (Table 16.2). 

Shen, M., Letiran, A., Xiao, Y., Golbraikh, A., Kohn, H., Tropsha, A. Quantitative structure-activity relationship analysis of functionalized amino acid anticonvulsant agents using k nearest neighbor and simulated annealing PLS methods./. Med. Chem. 2002, 45, 2811-2823. 

Use of acetophenone rather than benzaldehyde in the Knoevnagel condensation reaction affords the unsaturated ester, 13. Elaboration of this to the succinimide by a scheme analogous to that above leads to the anticonvulsant agent methsuximide (14)... 

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