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Modifications of antiepileptic drugs for improved tolerability and efficacy.

Landmark CJ, Johannessen SI - Perspect Medicin Chem (2008)

Bottom Line: The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds.Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity.These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders.

View Article: PubMed Central - PubMed

Affiliation: Cecilie Johannessen Landmark, Associate Professor, Dept. of Pharmacy, Faculty of Health Sciences, Oslo University College, Pilestredet 50, N-0167 Oslo, Norway.

ABSTRACT

Introduction: A large number of antiepileptic drugs (AEDs) are available today, but they may not be satisfactory regarding clinical efficacy, tolerance, toxicity or pharmacokinetic properties. The purpose of this review is to focus upon the rationale behind the chemical modifications of several recently marketed AEDs or drugs in development and to categorize them according to the main purposes for the improvements: better efficacy or tolerability accompanied by improved pharmacokinetic properties.

Material and method: AEDs that have been chemically modified to new derivatives during the last years are reviewed based on recent publications and PubMed-searches.

Results and discussion: Improvement in pharmacokinetic parameters may affect both tolerability and efficacy. Modifications to improve tolerability include various valproate analogues, divided into aliphatic amides, cyclic derivatives or amino acid conjugates. Furthermore, there are the carbamazepine analogues oxcarbazepine and eslicarbazepine, the felbamate analogues fluorofelbamate and carisbamate (RWJ 33369), and the lamotrigine analogue JZP-4. The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds. Other new drugs have new mechanisms of action related to GABA and glutamate receptors; the glutamate antagonists like topiramate (talampanel and NS-1209), and GABA(A) receptor agonists, benzodiazepine or progesterone analogues (ELB-139 and ganaxolone).

Conclusion: Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity. These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders.

No MeSH data available.


Related in: MedlinePlus

The main inhibitory and excitatory amino acid neurotransmitters in the brain, GABA and glutamate, respectively.
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f7-pmc-2008-021: The main inhibitory and excitatory amino acid neurotransmitters in the brain, GABA and glutamate, respectively.

Mentions: One way to improve efficacy of AEDs is by designing a better pharmacodynamic profiles with more specific mechanisms of action based on new pathophysiological findings. New AEDs in development will hopefully result in better chemical and pharmacological characteristics than the existing substances. The proposed mechanisms of action of these drugs are illustrated in the synapses by the main inhibitory neurotransmitter GABA and the main excitatory neurotransmitter glutamate with their main targets for pharmacological action (Fig. 1). The main pharmacodynamic mechanisms responsible for the clinical efficacy of AEDs include increased GABAergic or decreased glutamatergic neurotransmission, inhibition of voltage-gated ion channels or modifications of intracellular signalling pathways (Rogawski and Löscher, 2004b; Johannessen Landmark, 2007b). A common result of pharmacological intervention with these drugs is a decrease in neuronal excitability. The main modifications of AEDs and their main achievements are listed in Table 1. Most AEDs bind to target macromolecules where the neurotransmitters GABA or glutamate bind, such as receptors and transporters, or to voltage-gated ion channels. Structurally, some of the AEDs may have structural similarities with these amino acid neurotransmitters (Fig. 7), such as gabapentin. Most AEDs have several target molecules in common with the endogenous neurotransmitters (receptors, enzymes, reuptake proteins). In addition, pregabalin and gabapentin are structurally related to GABA.


Modifications of antiepileptic drugs for improved tolerability and efficacy.

Landmark CJ, Johannessen SI - Perspect Medicin Chem (2008)

The main inhibitory and excitatory amino acid neurotransmitters in the brain, GABA and glutamate, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2746576&req=5

f7-pmc-2008-021: The main inhibitory and excitatory amino acid neurotransmitters in the brain, GABA and glutamate, respectively.
Mentions: One way to improve efficacy of AEDs is by designing a better pharmacodynamic profiles with more specific mechanisms of action based on new pathophysiological findings. New AEDs in development will hopefully result in better chemical and pharmacological characteristics than the existing substances. The proposed mechanisms of action of these drugs are illustrated in the synapses by the main inhibitory neurotransmitter GABA and the main excitatory neurotransmitter glutamate with their main targets for pharmacological action (Fig. 1). The main pharmacodynamic mechanisms responsible for the clinical efficacy of AEDs include increased GABAergic or decreased glutamatergic neurotransmission, inhibition of voltage-gated ion channels or modifications of intracellular signalling pathways (Rogawski and Löscher, 2004b; Johannessen Landmark, 2007b). A common result of pharmacological intervention with these drugs is a decrease in neuronal excitability. The main modifications of AEDs and their main achievements are listed in Table 1. Most AEDs bind to target macromolecules where the neurotransmitters GABA or glutamate bind, such as receptors and transporters, or to voltage-gated ion channels. Structurally, some of the AEDs may have structural similarities with these amino acid neurotransmitters (Fig. 7), such as gabapentin. Most AEDs have several target molecules in common with the endogenous neurotransmitters (receptors, enzymes, reuptake proteins). In addition, pregabalin and gabapentin are structurally related to GABA.

Bottom Line: The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds.Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity.These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders.

View Article: PubMed Central - PubMed

Affiliation: Cecilie Johannessen Landmark, Associate Professor, Dept. of Pharmacy, Faculty of Health Sciences, Oslo University College, Pilestredet 50, N-0167 Oslo, Norway.

ABSTRACT

Introduction: A large number of antiepileptic drugs (AEDs) are available today, but they may not be satisfactory regarding clinical efficacy, tolerance, toxicity or pharmacokinetic properties. The purpose of this review is to focus upon the rationale behind the chemical modifications of several recently marketed AEDs or drugs in development and to categorize them according to the main purposes for the improvements: better efficacy or tolerability accompanied by improved pharmacokinetic properties.

Material and method: AEDs that have been chemically modified to new derivatives during the last years are reviewed based on recent publications and PubMed-searches.

Results and discussion: Improvement in pharmacokinetic parameters may affect both tolerability and efficacy. Modifications to improve tolerability include various valproate analogues, divided into aliphatic amides, cyclic derivatives or amino acid conjugates. Furthermore, there are the carbamazepine analogues oxcarbazepine and eslicarbazepine, the felbamate analogues fluorofelbamate and carisbamate (RWJ 33369), and the lamotrigine analogue JZP-4. The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds. Other new drugs have new mechanisms of action related to GABA and glutamate receptors; the glutamate antagonists like topiramate (talampanel and NS-1209), and GABA(A) receptor agonists, benzodiazepine or progesterone analogues (ELB-139 and ganaxolone).

Conclusion: Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity. These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders.

No MeSH data available.


Related in: MedlinePlus