Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 13, Issue 2, 2013

Zataria multiflora is an Iranian endemic plant with a variety of uses. Anticonvulsant effect of the plant has not been studied yet. We aimed to evaluate the anticonvulsant effect of the essential oil and methanolic extract of the plant on chemical and electrically seizures. Methods: Essential oil (EO) and methanolic extract (ME) were prepared by hydrodistillation and maceration method respectively and administered for evaluating the anticonvulsant activity against pentylenetetrazole (PTZ) and maximal electroshock (MES) convulsions in mice. Different doses of the EO and ME of Zataria multiflora were administered intraperitoneally (i.p), thirty minutes before induction of chemical (PTZ, 100 mg/kg) and electrical (50 mA, 50 Hz, 1 s duration) convulsions. Neurotoxicity was evaluated using rota-rod test. Mortality was determined after 24 hours for determining LD50. Results: EO significantly increased the onset time of clonic seizures at doses of 0.2, 0.25 and 0.35ml/kg and significantly prevented tonic convulsions induced by PTZ at the same doses. No increase in onset time of tonic convulsions was observed. Methanolic extract of Z. multiflora was not effective in PTZ model. Neither EO nor ME was effective against MES convulsions; however both of them significantly reduced the time spent on rota-rod at doses of 0.6 ml/kg and 3 g/kg respectively. LD50 value of the EO was determined as 1.30 (1.0-1.5) ml/kg. No mortality was seen for the ME until dose of 5 g/kg. Conclusion: EO would be a good candidate for more investigations to determine its active constituent(s) and also its mechanism against PTZ-induced seizures.

Serotonin2c (5-HT2C) receptors are widely expressed in the central nervous system where they play a pivotal role in the regulation of neuronal network excitability. Along with this fundamental physiological function, 5-HT2c receptors are thought to be implicated in the pathophysiology of several neuropsychiatric disorders and have become a major pharmacological target for the development of improved treatments of these disorders. In the past decade, many studies have focused on the constitutive activity of 5-HT2c receptors and the therapeutic potential of drugs acting as inverse agonists. Although the constitutive activity of the 5-HT2c receptor has been clearly described in vitro, the transposition of this concept to living animals is often difficult to ascertain. Nevertheless, cumulating evidence has demonstrated the functional relevance of such property in regulating physiological systems in vivo both at the level of the central and peripheral nervous systems. The present review provides an update of the growing number of studies that show, by means of pharmacological tools, the participation of the constitutive activity of 5-HT2c receptors in the control of various biochemical and behavioural functions in vivo and emphasizes the functional organization of this constitutive control together with the phasic and tonic (involving the spontaneous release of 5-HT) modalities of the 5-HT2c receptor in the brain.

Xanthine Oxidase (XO; EC. 1.1.3.22) and Dihydropyrimidine Dehydrogenase (DPD; EC. 1.3.1.2) are two enzymes responsible for the last steps of purine and pyrimidine catabolism, and hydroxylation of a wide variety of pyrimidine, pterin, and aldehyde substrates. Elion showed that purine isomers can be converted to various nucleotides, which influence pyrimidine metabolism (Elion, 1978). The current study is devoted to delineating the correlation between survival of human brain derived cells in culture and the activities of XO and DPD. Cultivation of (E90) brain cells was performed by the modified method of Mattson (1990). XO activity was measured by the formation of uric acid in the tissue. DPD activity was evaluated by the reduction of NADPH and the associated absorbance decrease at 320 nm. Cell death was detected by Trypan Blue dye leakage. During our investigation, we noticed a reversed correlation between the activities of XO and DPD over 12 days under normal conditions as well as in the presence of the XO and DPD inhibitors, allopurinol and dipyridamole. During the treatment period of 12 days, as well as from days 7-12 with the inhibitors, we observed cell protection, whereas treatment from days 1-7 elevated the percentage of dead cells in culture. A low dosage of allopurinol over 12 days also stimulated cell growth and increased their number in culture. We concluded that timely inhibition of XO as well as DPD activities might initiate cell growth and prevent their death. However, the main influence as the final enzyme of purine metabolism in the processes of cell proliferation belongs to XO in contrast to DPD.

Tumors of the central nervous system are the third most common type of childhood cancers. Brain tumors occur in children and adults; however pediatric patients require a different treatment process. Thirteen drugs similar to mechlorethamine are analyzed in this study. These drugs possess molecular properties enabling substantial and successful access to tumors of the central nervous system. All drugs exhibit zero violations of the Rule of 5, which indicate favorable bioavailability. Ranges in Log P, formula weight, and polar surface area for these drugs are: 1.554 to 3.52, 156.06 to 460.45, and 3.238 Angstroms2 to 45.471 Angstroms2, respectively. Hierarchical cluster analysis determined that agents 7 and 12 are most similar to the parent compound mechlorethamine. The mean values of Log P, formula weight, polar surface area, and molecular volume are 2.25, 268.51, 16.57 Angstroms2, and 227.01 Angstroms3, respectively. Principal component analysis indicates that agents 7 and 12 are most similar to mechlorethamine and multiple regression analysis of molecular properties produced a model to enable the design of similar alkylating agents. Values of Log (Cbrain/Cblood) indicate these agents will have very high permeation into the central nervous system.

Polyamines are compounds that interact with ionotropic receptors, mainly modulating the NMDA receptor, which is strictly related to many neurologic diseases such as epilepsy. Consequently, polyamines rise as potential neuropharmacological tools in the prospection of new therapeutic drugs. In this paper, we report on the biological activity of synthetic polyamine Mygalin, which was tested as an anticonvulsant in model of chemically induced seizures. Male Wistar rats were injected with vehicle, diazepam, MK-801 or Mygalin at different doses followed by Pentylenetetrazole or N-Methyl-D-Aspartate administration. Mygalin presented protection against seizures induced by both NMDA injections and PTZ administration by 83.3% and 16.6%, respectively. Moreover, it prolonged the onset of tonic-clonic seizures induced by PTZ. Furthermore, it was tested in neuroethological schedule evaluating possible side-effects and it presented mild changes in Open Field, Rotarod and Morris Water Maze tests when compared to available anticonvulsant drugs. The mechanism underlying the anticonvulsant effect of Mygalin is noteworthy of further investigation, nevertheless, based on these findings, we hypothesize that it may be wholly or in part due to a possible NMDA receptor antagonism. Altogether, the results demonstrate that Mygalin has an anticonvulsant activity that may be an important tool in the study of prospection of therapeutics in epilepsy neuropharmacology.

A series of twelve compounds (Compounds RNH1-RNH12) of acid hydrazones of pyridine-3-carbohydrazide or nicotinic acid hydrazide was synthesized and evaluated for anticonvulsant activity by MES, scPTZ, minimal clonic seizure and corneal kindling seizure test. Neurotoxicity was also determined for these compounds by rotarod test. Results showed that halogen substitution at meta and para position of phenyl ring exhibited better protection than ortho substitution. Compounds RNH4 and RNH12, were found to be the active analogs displaying 6Hz ED50 of 75.4 and 14.77 mg/kg while the corresponding MES ED50 values were 113.4 and 29.3 mg/kg respectively. In addition, compound RNH12 also showed scPTZ ED50 of 54.2 mg/kg. In the series, compound RNH12 with trifluoromethoxy substituted phenyl ring was the most potent analog exhibiting protection in all four animal models of epilepsy. Molecular docking study has also shown significant binding interactions of these two compounds with 1OHV, 2A1H and 1PBQ receptors. Thus, N-[(meta or para halogen substituted) benzylidene] pyridine-3-carbohydrazides could be used as lead compounds in anticonvulsant drug design and discovery.

In continuance of our search for anticonvulsant agents, we reported herein the synthesis, characterization and anticonvulsant evaluation of some newer semicarbazone analogues. A few compounds were also screened for neuroprotection assay. Some of the compounds showed significant anticonvulsant activity. Compound 4a showed 25% (1/4, 0.25 h), 75% (3/4, 0.5 & 2.0 h) and 100% (4/4, 1.0 h) protection against 6 Hz psychomotor seizure test at 100 mg/kg devoid of any neurotoxicity. Compound 4d showed neuroprotection activity with 26.3 ± 2.3 percent of total propidium iodide uptake at 100 µM and IC50 of the compound was calculated using dose response curve by probit analysis and was found to be 149 ± 1.22 µM.

Semicarbazones are synthesized by the condensation of semicarbazide and aldehyde/ketone. The literature survey revealed that semicarbazones had been emerged as compounds with diverse biological activities including anticonvulsant, antitubercular, anticancer, and antimicrobial activities. The anticonvulsant activity of semicarbazones is mainly attributed due to the presence of an aryl binding site with aryl/alkyl hydrophobic group, a hydrogen bonding domain and an electron donor group and they are suggested to act by inhibiting sodium ion (Na+) channel. Dimmock et al., reported an extensive series of semicarbazones and reported 4-(4-fluorophenoxy) benzaldehyde semicarbazone (C0102862, V102862) as lead molecule. In MES (oral) screening C0102862 showed protective index (PI > 315) more than carbamazepine (PI 101), phenytoin (PI > 21.6) and valproate (PI > 2.17). This review briefly describes the information available about semicarbazone analogs and their anticonvulsant activity.