Anticonvulsant activity

GABA site is occupied, and chloride channels open 

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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. 

Benzodiazepines. Several BZs have anticonvulsant activity and ate used for the treatment of epilepsy producing their anticonvulsant actions via interactions with the GABA /BZ receptor complex to enhance inhibitory GABAergic transmission (1). The anticonvulsant actions of the BZs tend to tolerate upon chronic usage in six months, and BZs also lead to withdrawal symptomatology. Other side effects include sedation, ataxia, and cognitive impairment. 

No natural products or their analogues are included among the pyridopyridazines, but several interesting biologically active compounds have emerged. Some l-chloro-4-hydrazino- and 4-chloro-l-hydrazino-pyrido[2,3-d]pyridazines (460) are very active hypotensives, whilst related dialkoxy compounds have anticonvulsant activity (65CPB586). 

As we have seen previously, succinimides containing a quaternary carbon form the basis for a series of anticonvulsant drugs. In the course of research in this series, it was found that the inclusion of additional hetero atoms in the ring was quite compatible with anticonvulsive activity. We consider here the oxa-zolidinediones a discussion of the hydantoins is found later in this section. 

The anticonvulsant activity of some 1,3-benzisoxazoles was discovered in routine testing. One of the more interesting of the subsequent analogues prepared was zonisamide (39). One of its syntheses starts with l,2-benzisoxazole-3-acetic acid (36) which is brominated and subsequently decarboxylated to give 37. Displacement of halogen in 37 with sodium bisulfite interestingly... 

The anticonvulsant activity of a drug may also be evaluated by measuring its ability to raise the convulsive threshold, i.e. the amount of applied current or infused PTZ required to just evoke a seizure. Comparison of the efficacy of drugs in the threshold and maximal seizure tests may distinguish between their abilities to raise seizure threshold or reduce seizure spread and development. 

One unwanted side-effect of phenytoin is its anti-folate activity. A programme of synthetic chemistry to manipulate the structure of the anti-folate compound pyri-methium to try to replace that property with anticonvulsant activity resulted in the synthesis of lamotrigine. It proved to be an effective AED in partial and generalised epilepsy but experience has found it also to be of value in absence seizures. 

DIBENZOCYCLOHEPTANES AND DIBENZOCYCLOHEPTENES Drugs in this structural class have effected a revolution in the treatment of severely depressed patients such that deinstitutionalization is a feasible public policy. The compounds often show other CNS activities which depend on the length of the side chain. One-carbon chains generally lead to anticonvulsant activity amines separated from the nucleus by three carbons usually donvey antidepressant activity. Selected examples possess significant anticholinergic activity. 

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... 

The sultam, sulthiame (170), shows anticonvulsant activity. p-Aminobenzenesulfonamide can be alkylated by w-chlorobutylsulfonyl chloride (168) in... 

Bienvenu E, Amabeoku GJ, Eagles PK, Scott G, Springfield EP. Anticonvulsant activity of aqueous extract of Leonotis leonurus. Phytomedicine 2002 9 217-223. 

Valproic acid is the common name for 2-propylpentanoic acid (Epival usually used as its sodium salt), also referred to as n-dipropylacetic acid, is a simple branched-chain carboxylic acid with unique anticonvulsant properties. Valproic acid was first synthesized in 1882 by Burton [75], but there was no known clinical use until its anticonvulsant activity was fortuitously discovered by Pierre Eymard in 1962 in the laboratory of G. Carraz, which was published by Meunier et al. in 1963 [76]. 

Further new competitive AMPA antagonists include the imidazo-fused 23-benzodiazepine derivative 103. This compound showed excellent anticonvulsant activity and other activities indicative of possible therapeutic significance in human stroke and Parkinson k disease <00BMC2127>. An efficient synthesis of fluorine-containing H-1,4-diazepino[6,5-/t]quinolines has been described based on iV,/V-dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine and an aromatic nucleophilic displacement with 1,2-ethylenediamine, followed by cyclocondensation <00S1822>. 

Effects of adenosine that have been attributed to activation of central A receptors include sedation, anticonvulsant activity, analgesia and neuroprotection. Adenosine... 

Bolvig, T., Larsson, O. M., Pickering, D., Nelson, N., Falch, E., Krogsgaard-Larsen, P., and Schousboe, A. (1999) Action of bicyclic isoxazole GABA analogues on GABA transporters and its relation to anticonvulsant activity. Eur. J. Pharmacol. 375, 361-31 A. 

White, H. S., Sarup, A., Bolvig, T., et al. (2002) Correlation between anticonvulsant activity and inhibitory action on glial gamma-aminobutyric acid uptake of the highly selective mouse gamma-aminobutyric acid transporter 1 inhibitor 3-hydroxy-4-amino-4,5,6,7-tetrahydro-l,2-benzisoxazole and its N-alkylated analogs. J. Pharmacol. Exp. Ther. 302, 636-644. 

White, H. S., Hunt, J., Wolf, H. H., Swinyard, E. A., Falch, E., Krogsgaard-Larsen, R, and Schousboe, A. (1993) Anticonvulsant activity of the gamma-aminobutyric acid uptake inhibitor N-4,4-diphenyl-3-butenyl-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol. Eur J. 

In the United States, anticonvulsant properties have been found in a series of l-methyl-2-phenylcarbamoylpiperidazines [182], The introduction of a methylene bridge into the hexahydro-l,2-diazine system of these compounds has been reported to lead to 2,3-diazabicyclo[2.2.1]heptane congeners with significantly reduced anticonvulsant activity [183]. 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

A series of branched aliphatic amides were prepared to evaluate the role of amide hydrolysis on the pharmacokinetics and anticonvulsant activity of valpromide analogues. Table 4.1 summarizes the structures investigated, the fraction of amide hydrolyzed (/m), and the stability in blood. These results were obtained after intravenous administration to dogs [6], The structures are classified here in order of decreasing fm. 

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