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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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Davis MDCH 5210 - Anticonvulsants 2006
Anticonvulsant tests - Major Seizure classes :
Anticonvulsant tests:
Partial
Generalized Absence
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Davis MDCH 5210 - Anticonvulsants 2006
Classification of Seizures
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Davis MDCH 5210 - Anticonvulsants 2006
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 don’t 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.
Drugs:
Carbamazepine
Phenytoin
Phenobarbital
Primidone
Valproate
Gabapentin
Lamotrigine
Zonisamide
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Davis MDCH 5210 - Anticonvulsants 2006
Drugs effective against scMET seizures:
These act at the seizure focus and may also prevent spread of seizure.
Interaction at Ca+2 channels. May also have some general membrane protein
effect, or act at GABA receptors. Clonazepam is sometimes used.
Drugs:
Ethosuximide
Clonazepam
Valproate
Lamotrigine?
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Davis MDCH 5210 - Anticonvulsants 2006
Seizures and Drugs.
Valproate
Lamotrigine
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Davis MDCH 5210 - Anticonvulsants 2006
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.
[ox]
O O
O O
O O
HN NH
H N NH
HN NH 2 2
O
phenylethylmalondiamide
Primidone Phenobarbital
PEMA
Ph H
Ph H
H
Ph N
N
O
O O N
O N
CH CH
H 2 3
11
Ethotoin
Phenytoin (Dilantin)
CH
3 CH
3
H C
3
O
O N O
O N
H
CH
3
Benzodiazepines
Clonazepam and Clorazepate are good for scMET induced seizures, not so good for MES
seizures. Diazepam is used for status epilepticus.
H CH
H 3
O O
O
N N
N
- +
COO K
O N N N
Cl
2 Cl N
Cl
Clonazepam
Clorazepate Diazepam
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Davis MDCH 5210 - Anticonvulsants 2006
Miscellaneous/Important mechanisms of action:
-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.
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Davis MDCH 5210 - Anticonvulsants 2006
Structures
Cl
Cl
N
N
H N O
2 H N N NH
2 2
Carbamazepine
Lamotrigine
S O
O
CH OSO NH
2 2 2
O O N OH
CH CH
3 3
O O
Topiramate (Topamax)
Tiagabine (Gabitril)
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More Stuctures
CH CH CH
3 2 2
CH COOH
HOOC NH
2
CH CH CH
3 2 2
γ -vinyl-GABA
Valproate
NH COOH
2
Baclofen
Gabapentin
SO2 NH2
Zonisamide (Zonegran)
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Davis MDCH 5210 - Anticonvulsants 2006
MedChem/Drug Design
The “linker” region has been proposed to interact with a positive region
of the GABA transporter.
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Davis MDCH 5210 - Anticonvulsants 2006
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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Davis MDCH 5210 - Anticonvulsants 2006
Summary of Anticonvulsants - AED’s
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