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Printable Handouts
Navigable Slide Index
- Introduction
- A chemical structure of Levetiracetam
- Originally discovered in sound-sensitive mice
- Antiepileptic drug discovery
- Inactivity in MES and s.c. PTZ seizure tests
- Levetiracetam in electroshock and PTZ seizures
- Protection against seizures in rat model
- Levetiracetam activity in GAERS model
- High therapeutic index of Levetiracetam
- No negative impact on cognitive function (1)
- No negative impact on cognitive function (2)
- Hyper-synchronization/excitability inhibition in vitro
- Levetiracetam inhibits hyper-synchronization
- Effect on development of amygdala kindling
- Effect on seizures in genetic models of epilepsy
- Chemical structure and pharmacological profile
- Mechanisms targeted in AED discovery (1)
- Inactivation of sodium channels
- Reduction of current through T-type Ca channels
- No conventional GABAergic effects
- Mechanisms targeted in AED discovery (2)
- Levetiracetam mechanism of action (1)
- Levetiracetam mechanism of action (2)
- Levetiracetam binding site - novel radioligand
- Levetiracetam binding site - characteristics
- SV2 proteins: candidates for the LEV binding site
- SV2 proteins knockout studies
- SV2A cloning and binding studies
- Affinities for hSV2A and anti-seizure potencies
- SV2A - novel intracellular and presynaptic target
- SV2A - broad-spectrum anticonvulsant target
- Kindling acquisition in SV2A (+/-) mice
- Levetiracetam studies in SV2A (+/-) mice (1)
- Levetiracetam studies in SV2A (+/-) mice (2)
- Target validation of SV2A
- Profile of new class of antiepileptic drugs
Topics Covered
- Levetiracetam
- Antiepileptic Drug Discovery
- Levetiracetam in electroshock and PTZ seizures
- Protection against seizures in rat model
- Levetiracetam activity in GAERS model
- Impact on cognitive function
- Hyper-synchronization / excitability inhibition in vitro
- Effect on development of amygdala kindling
- Effect on seizures in genetic models of epilepsy
- Inactivation of sodium channels
- Reduction of current through T-type Ca channels
- Levetiracetam mechanism of action
- SV2 proteins: candidates for the LEV binding site
- SV2A cloning and binding studies
- Levetiracetam studies in SV2A (+/-) mice
- Profile of new class of antiepileptic drugs
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Klitgaard, H. (2013, March 28). Discovery of Levetiracetam (Keppra(R)): The first SV2A ligand for the treatment of epilepsy [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 8, 2024, from https://doi.org/10.69645/UAGV8849.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Henrik Klitgaard has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Pharmaceutical Sciences
Transcript
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0:00
My name is Henrik Klitgaard.
I am a PhD research fellow
within the Neuroscience
Therapeutic Area at UCB.
The purpose of this
presentation is to share
with you the drug
discovery story of
levetiracetam that led
to the identification of
the first SV2A ligand for
the treatment of epilepsy.
0:24
Levetiracetam is a
pyrrolidine derivative with
high solubility and relatively
low molecular weight.
This chemical structure is novel
and different from all
other antiepileptic drugs.
0:39
The anti-epileptic
potential of levetiracetam
was originally discovered
by random screening
showing a potent ability to
protect against all phases
of seizure activity induced by
an acoustic stimulus in
sound-sensitive mice.
Levetiracetam showed a
protective ED_50 value of
17 mg per kilo
against clonic convulsions
after IP administration.
Levetiracetam, the
S-enantiomer, remains
active after a central
injection into the brain,
whereas the R-enantiomer and
the main metabolite lacks
activity in this model,
suggesting that the obtained
seizure suppression
relates to a central
action of levetiracetam.
1:26
Maximal electroshock
seizures, MES seizures,
have for several
decades been one of
the two conventional
screening models
in the search for new
antiepileptic drugs.
Later, PTZ seizures
also became involved
in the search for
anticonvulsant drugs.
Their most extensive use
has probably been in
the Antiepileptic Drug
Development Program at NIH,
in which several
thousands of compounds
have been screened since 1975
based on the
anticonvulsant activity
in these two models.
The table on this
slide illustrates data
from these two tests
obtained in mice
with the classical drugs
currently prescribed
for the treatment of epilepsy.
All these drugs are
able to generate
an effective dose protecting
50% of the animals,
an ED_50 value,
either against tonic hindlimb
extension in the MES test,
or against clonic convulsions
in this CD_97 PTZ test.
Therefore, it has
been assumed that all
potential drugs will reveal
anticonvulsant activity
in at least one of
these two tests.
Furthermore, the activity
profile of these drugs in
the two tests or spectrum
effect of valproate,
selective action of
phenytoin and carbamazepine
in the MES test and the
inverse for ethosuximide
together with their established
clinical efficacy as
nearest the assumption that
the MES test predict efficacy
against generalized tonic-clonic
and partial seizures in men,
and that the CD_97 PTZ
test predicts efficacy
against generalized absence
and mild clonal seizures.
It was therefore a
major complication
to the discovery efforts of
levetiracetam that the drug
was shown to be inactive
in both of these tests,
as shown on the next slide.
This slide contains
the same table
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