The Pharmacology of Imepitoin: The First Partial Benzodiazepine Receptor Agonist Developed for the Treatment of Epilepsy

@article{Rundfeldt2013ThePO,
  title={The Pharmacology of Imepitoin: The First Partial Benzodiazepine Receptor Agonist Developed for the Treatment of Epilepsy},
  author={Chris Rundfeldt and Wolfgang L{\"o}scher},
  journal={CNS Drugs},
  year={2013},
  volume={28},
  pages={29-43}
}
Although benzodiazepines (BZDs) offer a wide spectrum of antiepileptic activity against diverse types of epileptic seizures, their use in the treatment of epilepsy is limited because of adverse effects, loss of efficacy (tolerance), and development of physical and psychological dependence. BZDs act as positive allosteric modulators of the inhibitory neurotransmitter GABA by binding to the BZD recognition site (“BZD receptor”) of the GABAA receptor. Traditional BZDs such as diazepam or… 

Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy

TLDR
Several compounds with more selective action on GABA A receptors have the potential to become effective drugs against specific subtypes of focal-onset epilepsy, but their development needs time, and in the near future only one or two new GABA A agonists to obtain marketing authorization for focal epilepsy.

Investigating the potential of the anti-epileptic drug imepitoin as a treatment for co-morbid anxiety in dogs with idiopathic epilepsy

TLDR
Imepitoin does not appear to improve anxiety-related behaviour in dogs with IE treated with this medication for its anti-epileptic effects; however, imepitoin did not appear effective in reducing seizure frequency in a minority of cases.

Pharmacological Profile of the Novel Antiepileptic Drug Candidate Padsevonil: Characterization in Rodent Seizure and Epilepsy Models

TLDR
Padsevonil demonstrated robust efficacy across a broad range of rodent seizure and epilepsy models, several representing drug-resistant epilepsy, and its efficacy extended beyond the combination of drugs interacting separately with SV2 or the benzodiazepine site.

The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond

TLDR
Knowing knowledge of the pharmacokinetics, antiseizure efficacy and spectrum, and adverse effect profiles of currently used ASMs is an essential component of treating epilepsy successfully and maintaining a high quality of life for every patient, particularly those receiving polypharmacy for drug-resistant seizures.

Pharmacological Profile of the Novel Antiepileptic Drug Candidate Padsevonil: Interactions with Synaptic Vesicle 2 Proteins and the GABAA Receptor

TLDR
Padsevonil is a first-in-class AED candidate with a unique target profile allowing for presynaptic and postsynaptic activity and displayed nanomolar affinity for the three synaptic vesicle 2 protein isoforms and micromolar affinityFor the benzodiazepine binding site on GABAA receptors.

GABA Receptors: Pharmacological Potential and Pitfalls.

TLDR
The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.

International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans

TLDR
An up-to-date review on the currently available GABAA receptor subtype-selective ligands and proposals for the future development of ligands with better anxioselectivity in humans are made.
...

References

SHOWING 1-10 OF 67 REFERENCES

Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders.

TLDR
Comparison of fractional receptor occupancy required for the various effects of both full and partial agonists confirm earlier suggestions that receptor reserves for the individual effects differ with the same order.

Partial agonists of the benzodiazepine receptor: from animal data to results in patients.

  • W. Haefely
  • Biology
    Advances in biochemical psychopharmacology
  • 1988
TLDR
Concepts are presented here that could explain the modulatory function of the BZR, and a number of factors are proposed to determine the pharmacological and therapeutic profile of B zR ligands: intrinsic efficacy at the BzR, density of GABAA-BZR on neurons, functional reserve in GAB AA-BzRs, the intensity of the GABAergic input to a neuron, and the excitatory neuronal state.

Abecarnil: a novel anxiolytic with mixed full agonist/partial agonist properties in animal models of anxiety and sedation.

TLDR
It is shown that with the discovery of a number of subtypes of y-amino- butyric acid type A (GABAA) receptors, a second approach has become feasible to achieve a better dissociation of the effects of benzodiazepine-receptor ligands.

Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?

TLDR
There is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site, and it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzdiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABAA receptor subtypes.

Anxioselective anxiolytics: on a quest for the Holy Grail.

  • P. Skolnick
  • Biology
    Trends in pharmacological sciences
  • 2012

Characterization in Rats of the Anxiolytic Potential of ELB139 [1-(4-Chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a New Agonist at the Benzodiazepine Binding Site of the GABAA Receptor

TLDR
Evaluating the pharmacological profile of ELB139 in different models of anxiety concluded that it elicits strong effects on anxiety-related behavior in rats mediated by its benzodiazepine-like activity without showing sedation or the development of tolerance, a major side effect of Benzodiazepines.

Benzodiazepines on trial: a research strategy for their rehabilitation.

...