Current Topics in Medicinal Chemistry - Volume 12, Issue 9, 2012

It has been my great pleasure to present before you the special issue that is intended to cover all major aspects of research devoted to the medicinal chemistry of anticonvulsant agents. The past few years have seen much progress in terms of research aiming to the new drug discovery of epilepsy. The number of publications in this field has risen steadily with novel and important results being reported in a variety of high impact factor journals. Epilepsy is a chronic neurological disorder of the brain that affects people in every country of the world. It is characterized by recurrent seizures - which are physical reactions to sudden, usually brief, excessive electrical discharges in a group of brain cells. Around 50 million people worldwide have epilepsy and interestingly nearly 90% of the people with epilepsy are found in developing regions. Recent studies in both developed and developing countries have shown that up to 70% of newly diagnosed children and adults with epilepsy can only be successfully treated. The search for new antiepileptic drug that is cheaper, safer and more effective continues to be an area of interest for the medicinal chemists worldwide. This special issue includes contributions from many leading figures in this area. First contribution to this issue is by Zuliani et al. who have identified the sodium channel blockers as a therapeutic target for treating epilepsy. Various currently used antiepileptic drugs that act by blocking the sodium channels have been described and it also covers the recently published literature on various anticonvulsant agents that act by blocking the sodium channel....

The voltage-gated sodium channels (VGSCs) are a family of membrane proteins forming a pore, through which they selectively conduct sodium ions inward and outward cell's plasma membranes in response to variations of membrane potentials, playing a fundamental role in controlling cellular excitability. Growing evidences suggest that abnormal VGSCs are involved in the pathophysiology of both acquired and inherited epilepsy. Approximately two dozen drugs are currently marketed for the treatment of epilepsy and most of them act as sodium channel blockers, preventing the return of the channels to the active state by stabilizing the inactive form. Despite the many drugs on the market, 30% of patients continue to experience seizures even in the presence of optimal doses of AEDs, while others continue to suffer from medication induced side effects. Thus, there is a great need to continue the search for new AEDs that are not only more effective, but also have a better side effects profile. For this reason, many efforts have been made in the recent years to identify new sodium channel blockers for the treatment of epilepsy. These studies have led to different classes of compounds, characterized by a great structural diversity. The aim of this review is to provide an introduction on the structure and function of the sodium channels, followed by a brief historical perspective on the sodium channel blockers in use as anticonvulsant drugs. Moreover, it will focus on the medicinal chemistry of the sodium channel blockers recently published (2008-2011) and the drug design/molecular modeling studies related to the receptor.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) controlling physiological processes as learning and memory. However, the overactivation of glutamatergic neurotransmission is often related to various CNS chronic and acute diseases (epilepsy, ischaemia, Parkinson, etc.). This review will focus on the chemical structures, mechanism of action and main structure-activity relationships of anticonvulsant agents acting through glutamate neurotransmission.

The role of free radical-mediated reactions in human neuropathology continues to attract significant interest. Oxidative injury produced by free radicals may play a role in the initiation and progression of epilepsy and, therapies aimed at reducing oxidative stress may ameliorate tissue damage and favorably alter the clinical course. The prevalence of epilepsy increases with age, and mitochondrial oxidative stress is a leading mechanism of aging and age-related degenerative disease, signifying a further involvement of mitochondrial dysfunction in seizure generation. Oxidative stress occurs when the generation of reactive oxygen species in a system exceeds the body's ability to neutralize and eliminate them, thus creating an imbalance or over abundance of free radicals. Therefore, it is imperative to maintain oxidative balance and control in the brain, and this is tightly regulated by antioxidants. In the last two decades, there has been an explosive interest in the role of antioxidants or neuroprotectants in clinical as well as experimental models of epilepsy. In this regard, the present review is intended to discuss the current state of knowledge pertaining to neuroprotection in epileptic conditions by employing diverse chemical agents including conventional as well as novel anti-epileptic drugs, and to highlight the efficacy of distinct neuroprotective strategies for preventing or treating epilepsy.

Synthesis of genome level expression data related to human epilepsy and animal models of epileptogenesis is a challenge because of differences in the use of animal species and strains, brain regions, methods to trigger epileptogenesis, tissue sampling time-points, epilepsy phenotype assessment, array platforms, normalization algorithms, cutoff points for identifying differentially expressed genes etc. Nevertheless, a comprehensive review of reported analysis identifies chemokine signaling and toll-like receptor signaling as convergent epileptogenic pathways. This transcriptomic evidence is supported by genome-wide association analysis in epilepsy, known effect of small molecules on gene expression, and cellular and molecular studies. The present review thus demonstrates that synthesis of diverse genome level expression analysis in complex brain disorders can identify promising leads in understanding the mechanisms underlying them.

Major advances in antiepileptic drug therapy have taken place since 1950s. In the first period, several antiepileptic drugs (AEDs) such as phenobarbital, diphenylhydantoin, ethosuximide, carbamazepine, benzodiazepines and valproic acid were introduced to epilepsy treatment. After 1990 many new generation drugs (lamotrigine, topiramate, gabapentine, pregabaline, felbamate, lacosamide, levetiracetam etc.) have been developed. These novel AEDs have offered some advantages such as fewer side effects, fewer drug-drug interactions, and better pharmacokinetic properties. But pharmacoresistance and therapeutic failure in 20-25% of the patients remain the main reasons to continue efforts to find safer and more efficacious drugs and ultimate a treatment for this devastating disease. Several AEDs especially novel compounds have been found to be effective also in the treatment of several other neurologic and psychiatric disorders. Chemical diversity of the newer antiepileptic drugs as well as those currently in clinical development is another point that encourages medicinal chemists to study this subject. This review summarizes recent studies on the development of potential anticonvulsant compounds in different chemical structures, their structure-activity relationships and also therapeutic usages of AEDs other than epilepsy.

The use of current antiepileptic drugs has been questioned due to the nonselectivity of the drugs and the undesirable side effects posed by them. This led to an intensive investigation in this area worldwide during the past 10 years. There have been some significant outcomes and the findings are promising as far as drug efficacy and safety is concerned. This review covers the new anticonvulsant agents that have shown encouraging activities and less neurotoxicity. A detailed pharmacology and pathophysiology of different types of epilepsy is described here with the structural classification of most active agents. The new structural classes of compounds may prove as lead molecules and good candidates for the future investigations.