Anticonvulsants structure-activity relationships

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],... 

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. 

Uracil and thymine are both reported to have electroshock anticonvulsant activity [371]. A series of 5- and 6-alkyl derivatives was prepared [373] and tested for electroshock as well as for metrazole protection [374]. It was found that most compounds of this type were active in the electroshock test. There is a trend toward increased activity with increased size of the alkyl groups, and introduction of 1,3-dimethyl substituents is also of benefit. Against metrazole-induced shock, however, there are no obvious structure-activity relationships. 

Hays, S.J., Rice, M.J., Ortwine, D.F., Johnson, G., Schwarz, R.D., Boyd, D.K., Copeland, L.F., Vartanian, M.G. and Boxer, P.A. (1994). Substituted 2-Benzothiazolamine as Sodium Flux Inhibitors Quantitative Structure-Activity Relationships and Anticonvulsant Activity. J.Pharm.ScL, 83,1425-1432. 

Klopman, G. and Raychaudhury, C. (1990). Vertex Indices of Molecular Graphs in Structure-Activity Relationships A Study of the Convulsant-Anticonvulsant Activity of Barbiturates and the Carcinogenicity of Unsubstituted Polycyclic Aromatic Hydrocarbons. J. Chem. Inf ComputSci.,30,12-19. 

Lien, E.J., Liao, R.C.H. and Shinouda, H.G. (1979). Quantitative Structure-Activity Relationships and Dipole Moments of Anticonvulsants and CNS Depressants. J.Pharm.Sci., 68, 463-465. 

Unverferth K, Engel J, Hofgen N, Rostock A, Gunther R, Lankau HJ, et al. Synthesis, anticonvulsant activity, and structure-activity relationships of sodium channel blocking 3-aminopyrroles. J Med Chem 1998 41 63-73. 

Hays SJ, Rice MJ, Ortwine DF, Johnson G, Schwarz RD, Boyd DK, et al. Substituted 2-benzothiazolamines as sodium flux inhibitors Quantitative structure-activity relationships and anticonvulsant activity. J Pharm Sci 1994 83 1425-32. 

Ivanciuc, O. (2004a) Similarity matrices quantitative structure-activity relationships for anticonvulsant phenylacetanilides. Internet Electron.]. Mol. Des., 3, 426-442. 

Mopman, G. and Raychaudhury C. (1990) Vertex indices of molecular graphs in structure-activity relationships a study of the convulsant— anticonvulsant activity of barbiturates and the carcinogenicity of unsubstituted polycyclic aromatic hydrocarbons. /. Chem. Inf. Comput. Sci., 30, 12-19. 

Quantitative Structure-Activity Relationship Analysis of Functionalized Amino Acid Anticonvulsant Agents Using k Nearest Neighbor and Simulated Annealing. 

Ho, B., Crider, A.M. and Stables, J.P. 2001. Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores. Eur. J. Med. Chem. 36(3) 265-286. 

These quantitative structure-factor relationships, at least for the first two factors representing two different basic effects which determine the main part of the biological activities, are well identified and interpretable. High values of the first factor representing simple reflexes and anticonvulsant action will result for compounds with low hydrophobicity of Ra and R r, an a-Me branch, no second Me or double-bonded substituents in a-position, and no branch at the P-C atom. 

Whether there is any other connection between anticonvulsant activity and camosine s antiaging actions is obviously highly speculative. It may be relevant to note that epileptic seizures and a shortened life span, together with altered protein accumulation, are consequences of PIMT-deficiency in mice, while treatment with valproic acid, an anticonvulsant, partially suppresses these symptoms including effects on life span (Yamamoto et ah, 1998). Conversely, PIMT overexpression can increase life span of Drosophila (Bennet et ah, 2003). Furthermore, the chemistry of some anticonvulsants (ethosuximide) resembles quite closely the structure of the succinimide intermediate formed during both asparagine deamidation and PIMT-mediated repair of isoaspartate residues. One conjectures whether there are any relationships between these... 

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