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Anticonvulsant Agents
Guest Editor: Barbara Malawska

Editorial Pp.1-2
Barbara Malawska
[Editorial In PDF]

Mechanisms of Action of Antiepileptic Drugs Pp.3-14
Piotr Czapinski, Barbara Blaszczyk, Stanislaw J. Czuczwar
[Abstract] [Full text article]

Voltage Gated ion Channels: Targets for Anticonvulsant Drugs Pp.15-30
Adam C. Errington, Thomas Stohr and George Lees
[Abstract] [Full text article]

AMPA Receptor Antagonists as Potential Anticonvulsant Drugs Pp.31-42
Giovambattista De Sarro, Rosaria Gitto, Emilio Russo, Guido Ferreri Ibbadu, Maria Letizia Barreca, Laura De Luca and Alba Chimirri
[Abstract] [Full text article]

Anticonvulsant and Antinociceptive Actions of Novel Adenosine Kinase Inhibitors Pp.43-58
Steve McGaraughty, Marlon Cowart, Michael F. Jarvis and Robert F. Berman
[Abstract] [Full text article]

Serotonergic 5-HT2C Receptors as a Potential Therapeutic Target for the Design Antiepileptic Drugs Pp.59-67
Methvin Isaac
[Abstract] [Full text article]

New Anticonvulsant Agents Pp.69-85
Barbara Malawska
[Abstract] [Full text article]

Abstracts

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Editorial
Barbara Malawska
[Editorial In PDF]

Anticonvulsant Agents

Epilepsy is a relatively common neurological condition, affecting 0.4-1% of the world’s population (45-100 million people). Conventional antiepileptic drugs (AEDs) are widely prescribed but induce a range of side effects. Furthermore, there is a significant group of patients (20-30%) resistant to the currently available therapeutic agents. During the past decade, several new drugs have been approved or are in the process of being approved. Despite the availability of new AEDs with a novel pharmacological mechanism of action, the efficacy of the treatment of epilepsy has not increased significantly over the recent years. Nevertheless, the new drugs have brought considerable improvement in the tolerability of anticonvulsant therapies. None of the currently approved AEDs are ideal and most are used as add-on therapies to the existing standard therapy and can be associated with chronic and acute adverse effects. Hence, the search for new AEDs continues.

In view of the upswing in research on basic molecular pharmacological studies and the development of new antiepileptic drugs in the recent years, a special issue of “Current Topic in Medicinal Chemistry” has been presented to review recent developments in this area. The topic of this issue is “New trends in anticonvulsant drug research”. The purpose of the current issue is to highlight the most important recent achievements in antiepileptic drug research, with emphasis on the discovery of novel drugs and the elucidation of their mechanisms of action. This issue presents articles from six groups of researchers who are involved in the investigation of the mechanisms of action and design of anticonvulsant agents.

Stanislaw J. Czuczwar, Piotr Czapin´ski and Barbara Bl/aszczyk open the issue with a review of the mechanisms of action of available antiepileptic drugs. In general, the efficacy of AEDs is due to several main activities, which include potentiation of inhibitory mechanisms (i.e., GABA-ergic transmission), inhibition of excitatory mechanisms (i.e. glutamatergic transmission) and inhibition of excessive firing of neurons (modulator of membrane action conductance via sodium, calcium or potassium channels). The majority of AEDs possess more than one mechanism of action, which may account for their efficacy. Novel antiepileptic drugs usually exhibit a better pharmacological profile in experimental epilepsy models than conventional antiepileptic drugs and also are better tolerated by epileptic patients, while being practically devoid of important pharmacokinetic drug interactions.

The second review by George Lees, Adam C. Errington and Thomas Stöhr focuses on elements that are crucial to determining the intrinsic excitability of neurons in the central nervous system, the voltage gated ion channels. The physiological roles of voltage gated ion channels that are selective for sodium, potassium and calcium conductance, as well as attempts to highlight their role in the pathology of epilepsy are reviewed. This is supplemented by presenting the mechanism of drug action at these important anticonvulsant targets for classical and clinically-relevant compounds (e.g. phenytoin, ethosuximide, carbamazepine) as well as some important second-generation drugs (e.g. lamotrigine, gabapentin, levetiracetam) and novel experimental agents (e.g. retigabine, losigamone, safinamide). The need for new drugs in this area and the potential of combinatorial methods and recombinant screening to identify leads are also discussed.

The next review, presented by Alba Chimirri, Giovambatista De Sarro, Rosaria Gitto, Emilio Russo, Guido Ferreri Ibbadu, Maria Letizia Barreca and Laura De Luca, describes competitive and noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor (AMPAR) antagonists able to prevent and/or block epileptic seizures in different animal models, proving to be potent anticonvulsant agents.

Two articles discuss the possible role of neurotransmitters such as adenosine and serotonin (5-hydroxytryptamine, 5-HT) as new rational targets for the development of novel antiepileptic drugs. The review presented by Steve McGaraughty, Marton Cowart, Michael F. Jarvis and Robert F. Berman briefly summarizes the role of the endogenous purine nucleoside, adenosine which acts as an inhibitory neuromodulator throughout the central and peripheral nervous system and can regulate seizure and nociceptive activity. The concentration and actions of endogenous adenosine depend on the primary metabolic enzyme, adenosine kinase. The authors review the recent development of structurally novel nucleoside and nonucleoside adenosine kinase inhibitors as potential therapeutic agents against pain and epileptic seizures, as well as other pathological conditions such as inflammation and cerebral ischemia.

The review by Methvin Isaac describes advancements in the research of mammalian 5-HT_2C receptor subtypes, specifically their structure, pharmacology, central nervous system distribution and actions at the molecular level. Empirical evidence, suggesting that serotoninergic 5HT_2C receptor subtypes may present a potential therapeutic target for the design of antiepileptic drugs, is discussed.

The final review describes new anticonvulsant agents, which represent various structures for which the precise mechanism of action is still not known.

I wish to thank Dr. Allen B. Reitz, for the invitation to be the Guest Editor of this special issue. I would like to offer my special thanks to all the eminent authors who have contributed to this issue with their hard work and dedication - this collection could not have been created without their input. I am indebted to them and have the utmost regard for their efforts.

Barbara Malawska
Jagiellonian University, Medical College
Department of Physicochemical Drug Analysis
Medyczna 9, 30-688 Kraków
Poland

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Mechanisms of Action of Antiepileptic Drugs
Piotr Czapinski, Barbara Blaszczyk and Stanislaw J. Czuczwar
[Full text article]

γ-Aminobutyric acid (GABA), one of the main inhibitory neurotransmitters in the brain, interacts with three types of receptors for GABA - GABA_A, GABA_B and GABA_C. GABA_A receptors, associated with binding sites for benzodiazepines and barbiturates in the form of a receptor complex, control opening of the chloride channel. When GABA binds to the receptor complex, the channel is opened and chloride anions enter the neuron, which is finally hyperpolarized. GABAB receptors are metabotropic, linked to a cascade of second messengers whilst the physiological meaning of ionotropic GABAC receptors, mainly located in the retina, is generally unknown. Novel antiepileptic drugs acting selectively through the GABA-ergic system are tiagabine and vigabatrin. The former inhibits neuronal and glial uptake of GABA whilst the latter increases the synaptic concentration of GABA by inhibition of GABA-aminotransferase. Gabapentin, designed as a precursor of GABA easily entering the brain, was shown to increase brain synaptic GABA. This antiepileptic drug also decreases influx of calcium ions into neurons via a specific subunit of voltage-dependent calcium channels. Conventional antiepileptics generally inhibit sodium currents (carbamazepine, phenobarbital, phenytoin, valproate) or enhance GABA-ergic inhibition (benzodiazepines, phenobarbital, valproate). Ethosuximide, mainly controlling absences, reduces calcium currents via T-type calcium channels. Novel antiepileptic drugs, mainly associated with an inhibition of voltage-dependent sodium channels are lamotrigine and oxcarbazepine. Since glutamate-mediated excitation is involved in the generation of seizure activity, some antiepileptics are targeting glutamatergic receptors – for instance, felbamate, phenobarbital, and topiramate. Besides, they also inhibit sodium currents. Zonisamide, apparently sharing this common mechanism, also reduces the concentration of free radicals.

Novel antiepileptic drugs are better tolerated by epileptic patients and practically are devoid of important pharmacokinetic drug interactions.

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Voltage Gated ion Channels: Targets for Anticonvulsant Drugs
Adam C. Errington, Thomas Stohr and George Lees
[Full text article]

Epilepsy is one of the most prevalent neurological syndromes in the world today. Epilepsy describes a group of brain disorders whose symptoms and causes are diverse and complicated, but all share a common behavioural manifestation: the seizure. Seizures result from the abnormal discharge of groups of neurons within the brain, usually within a focal point, that can result in the recruitment of large brain regions into epileptiform activity. Although the range of explanations for the development of seizures can be as varied as genetic composition to acute head trauma, the net result is often similar. The excitability of neurons is governed by the input they receive from their neighbours and the intrinsic excitability of the neuron. In this review we focus on elements that are crucial to determining the intrinsic excitability of neurons in the CNS, the voltage gated ion channels (VGICs).

VGICs as well as being important for physiological function are critical in producing hyperexcitability such as that associated with seizure discharges. Many drugs routinely used in the clinical setting, as well as several novel experimental drugs, have shown interactions with VGICs that underpin, at least in part, their anticonvulsant action. We review the physiological roles of voltage gated ion channels that are selective for sodium, potassium and calcium conductance and attempt to highlight their role in the pathology of epilepsy. This is supplemented by the mechanisms of drug action at these important anticonvulsant targets for classical and clinically relevant compounds (e.g. phenytoin, ethosuximide) as well as some important second generation drugs (e.g. gabapentin, levetiracetam) and novel experimental agents (e.g. retigabine, losigamone, safinamide). We also briefly discuss the urgent need for new drugs in this arena and the potential of combinatorial methods and recombinant screening to identify leads.

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AMPA Receptor Antagonists as Potential Anticonvulsant Drugs
Giovambattista De Sarro, Rosaria Gitto, Emilio Russo, Guido Ferreri Ibbadu, Maria Letizia Barreca, Laura De Luca and Alba Chimirri
[Full text article]

Over the last years a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) have been intensively studied owing to their crucial role in physiological and pathological processes. Efforts targeting AMPAR have been focused on identification of ligands as potential therapeutic agents useful in the prevention and treatment of a variety of neurological and non-neurological diseases. In particular, extensive work was addressed to the discovery of selective antagonists some of which proved to be potent anticonvulsant agents.

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Anticonvulsant and Antinociceptive Actions of Novel Adenosine Kinase Inhibitors
Steve McGaraughty, Marlon Cowart, Michael F. Jarvis and Robert F. Berman
[Full text article]

Adenosine (ADO) acts as an inhibitory neuromodulator throughout the central and peripheral nervous system and can regulate seizure and nociceptive activity. However, the positive actions of systemically administered ADO are usually accompanied by undesirable side effects such as hypomobility and cardio-suppression. Adenosine kinase (AK) is the primary metabolic enzyme regulating intra- and extracellular concentrations of ADO. We review the recent development of structurally novel nucleoside and nonnucleoside AK inhibitors that demonstrate high specificity for the AK enzyme. Several of these compounds have shown significant beneficial effects in animal models of epilepsy and pain with an improved preclinical therapeutic window over direct acting ADO receptor agonists.

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Serotonergic 5-HT2C Receptors as a Potential Therapeutic Target for the Design Antiepileptic Drugs
Methvin Isaac
[Full text article]

A variety of clinical observations suggest that certain forms of epilepsy are due to long-term, progressive changes in neural networks that eventually provoke spontaneous and recurring seizures. Recently, there has been growing evidence that serotonergic neurotransmission modulates experimentally induced seizures and is involved in the enhanced seizure susceptibility observed in some genetically epilepsy-prone animals. Generally, agents that elevate extracellular serotonin (5-Hydroxytryptamine, 5-HT) levels, such as 5-hydroxytryptophan, and 5-HT reuptake blockers inhibit both limbic and generalized seizures. Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically-evoked convulsions. More specifically, the recent finding that the 5-HT2B/2C receptor agonist, 1-(mchlorophenyl)- piperazine (mCPP) is anticonvulsant has kindled an interest into the investigation of the serotonergic 5- HT2C receptor subtype as a potential target for the treatment of epilepsy. Further pharmacological evaluation of selective activation or inactivation of the 5-HT2C receptor subtype with selective agonist/positive modulators and antagonists will provide important information about the therapeutic contribution of this receptor to the epileptic circuitry in the brain. Future development of serotonergic antiepileptic drugs will be a significant addition to the therapeutic armamentarium against epilepsy.

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New Anticonvulsant Agents
Barbara Malawska
[Full text article]

The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. This review describes new anticonvulsant agents representing various structures for which the precise mechanism of action is still not known. Many of the compounds presented in this review have been tested according to the procedure established by the Antiepileptic Drug Development Program of the Epilepsy Branch of the National Institute of Neurological Disorders and Stroke, National Institute of Health, USA. The newer agents include sulfonamides, amino acids, amides (analogs of γ-vinyl GABA, N-benzylamides, 2,6-dimethylanilides, carboxyamides, hydroxyamides, alkanoamides); heterocyclic agents ((arylalkyl)imidazoles, pyrrolidin-2,5-diones, lactams, semi- thiosemicarbazones, thiadiazoles, quinazolin-4(3H)-ones, 2,5-disubstituted 1,2,4-thadiazoles, xanthones, derivatives of isatin) and enaminones. These new structural classes of compounds can prove useful for the design of future targets and development of new drugs.