Anticonvulsants

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Anticonvulsants
Selective CNS drugs (Depressants), used to
treat epilepsy. These syndromes affect about 1
of the population. One would hope to have
anticonvulsants that affect pathologically
altered neurons of seizure foci, which would then
prevent or reduce their excessive discharge. The
way that anticonvulsants work is to reduce the
spread of excitation from seizure foci and
prevent detonation and disruption of function of
the normal neurons. The underlying pathology is
not affected. Idiopathic epilepsy No visible
pathology, yet abnormal neuronal firing takes
place and spreads throughout the brain. The
pattern of initiation and the extent of
propagation determines the type and severity of
the seizure.
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Anticonvulsant tests - Major Seizure classes
Anticonvulsant tests Strychnine blocks
glycine receptors Bicuculline GABA
antagonist Picrotoxin Blocks GABA Cl- ion
channels Maximal electroshock (MES) Pentylene
tetrazole (sc MET) Two Major Seizure
classes Partial Generalized Absence Note
Generalized tonic-clonic seizures respond to the
same drugs as partial seizures.
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Classification of Seizures
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Seizures and Drugs.
Valproate Lamotrigine
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Mechanisms
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GABA
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Na and Ca Channels
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MES Seizures
Drugs effective against MES seizures
Inhibitors of MES induced seizures are
indicative of action against partial seizures.
These compounds dont act at the seizure focus,
but prevent the spread of seizures. Mechanism of
action for MES inhibitors. Alter Na and K ion
conductances, interact with ion channels in
membranes. Some have a similar mechanism of
action to local anesthetics. SAR of partial
seizure/MES compounds Phenyl ring(s) are
necessary (first group). Example is
phenobarbital. Valproate is an exception because
it works for everything. Drugs Carbamazepine Phe
nytoin Phenobarbital Primidone Valproate Gabapent
in Lamotrigine Zonisamide
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Drugs effective against scMET seizures
These drugs are effective against absence
seizures. These act at the seizure focus and may
also prevent spread of seizure. Interaction at
Ca2 channels. May also have some general
membrane protein effect, or act at GABA
receptors. Clonazepam is sometimes
used. Drugs Ethosuximide Clonazepam Valproate La
motrigine?
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Seizures and Drugs.
Valproate Lamotrigine
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SAR-
Barbiturates and related compounds.-
Phenobarbital has been widely used. Other
barbiturates have no advantages, but the
phenyl-substituted barbiturates are effective.
SAR is the same as for sedative/hypnotic effects.
Hydantoins. Na channels
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SAR-2
Succinimides. Ca2 channels
Benzodiazepines Clonazepam and Clorazepate are
good for scMET induced seizures, not so good for
MES seizures. Diazepam is used for status
epilepticus.
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Miscellaneous/Important mechanisms of action
Carbamazepine (Tegretol, Carbatrol) Ineffective
against Met induced seizures, but is good for
mixed seizure patients in the partial group. Na
channels. Lamotrigine (Lamictal) Na channels.
Similar to phenytoin and carbamazepine. Valproat
e (Depakine) Broadest activity of all
antiepileptic agents. Affect Na channel
recovery and also increases GABA levels. May
stimulate synthesis or inhibit degradation. Gabap
entin (Neurontin) Promotes GABA release. Was
supposed to be a GABA agonist, but it doesnt
work that way. Baclofen may also work that
way. ?-vinyl GABA (vigabatrin), (Sabril).
Inhibits GABA transaminase. There are a number
of compounds that do this. Topiramate (Topamax)
- Mechanism is still unclear. Affects GABA Cl-
flux similar to BDZs, but is not inhibited by
Fumazenil. Not like barbiturates either.
Antagonizes non-NMDA glutamate receptors. Tiagabi
ne (Gabitril) - GABA reuptake inhibitor.
Interesting SAR Zonisamide (Zonegran) - Na
channels or Ca2 channels.
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Structures
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More Stuctures
Zonisamide (Zonegran)
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MedChem/Drug Design
Synthesis of Novel GABA Uptake Inhibitors. 3.
Diaryloxime and Diarylvinyl Ether Derivatives of
Nipecotic Acid and Guvacine as Anticonvulsant
Agents1Lars J. S. Knutsen, Knud Erik Andersen,
Jesper Lau, Behrend F. Lundt, Rodger F. Henry,
Howard E. Morton, Lars N?rum, Hans Petersen,
Henrik Stephensen, Peter D. Suzdak, Michael D. B.
Swedberg, Christian Thomsen, and Per O.
Srensen J. Med. Chem. 1999 42(18) pp 3447 -
3462
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MedChem/Drug Design-2
Model for SAR of GABA Reuptake Inhibitors. The
linker region has been proposed to interact
with a positive region of the GABA transporter.
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MedChem/Drug Design-3
Electrostatic potential calculations52 for
molecules 11, 12, and 13. The most
electronegative surface is represented by the red
shading (the linker is indicated by the red
arrows), graduating toward the electropositive
via yellow and green to blue as the most
electropositive. As proposed, the oxime 12 has a
less electronegative region in the linker than
the vinyl ether 13 both are significantly
different from the pentenyl analogue 11 of
tiagabine. This is reflected in their activities
as inhibitors of 3H-GABA uptake in vitro, which
are 335, 41, and 14 nM, respectively.
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Summary of Anticonvulsants - AEDs
A special game for pharmacy students. - Based on
Lettermans Know Your Current Events. Also
Know Your Cuts of Meat. Know your
seizure classes! Know your seizure inducers
(particularly MES, scMET) Know your mechanisms
(Na, Ca, GABA) Know your main drug structures,
know your phenyl rule Know your
benzodiazepines Know your principles of medicinal
chemistry drug design.