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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Davis MDCH 5210 - Anticonvulsants 2006
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 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.
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
Phenytoin
Phenobarbital
Primidone
Valproate
Gabapentin
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 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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Seizures and Drugs.
Valproate
Lamotrigine
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SARBarbiturates 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.
O
HN
[ox]
O
O
O
HN
NH
O
NH
H2N
O
Primidone
O
NH2
phenylethylmalondiamide
Phenobarbital
PEMA
Hydantoins. Na+ channels
Ph
Ph
O
Ph
H
H
N
N
O
H
Phenytoin (Dilantin)
O
H
N
N
O
CH2 CH3
Ethotoin
"less effective than phenytoin"
Davis MDCH 5210 - Anticonvulsants 2006
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Succinimides. Ca+2 channels
SAR-2
CH 3
CH 3
H3C
O
O
N
O
H
O
N
CH 3
Ethosuximide (Zarontin)
Phensuximide
(Not as good, but is anticonvulsant)
Benzodiazepines
Clonazepam and Clorazepate are good for scMET induced seizures, not so good for MES
seizures. Diazepam is used for status epilepticus.
H
H
O
N
CH3
O
N
-
COO K
O2N
N
Cl
N
O
N
+
N
Cl
Cl
Clonazepam
Clorazepate
Diazepam
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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.
Valproate (Depakine) – Broadest activity of all antiepileptic agents. Affect Na+ channel
recovery and also increases GABA levels. May stimulate synthesis or inhibit degradation.
Gabapentin (Neurontin) – Promotes GABA release. Was supposed to be a GABA agonist,
but it doesn’t 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 nonNMDA glutamate receptors.
Tiagabine (Gabitril) - GABA reuptake inhibitor. Interesting SAR
Zonisamide (Zonegran) - Na+ channels or Ca+2 channels.
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Structures
Cl
Cl
N
N
H2 N
O
Carbamazepine
O
CH2 OSO2 NH2
O
O
O
O
Topiramate (Topamax)
H2 N
N
N
NH 2
Lamotrigine
O
S
N
CH3
S
OH
CH3
Tiagabine (Gabitril)
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More Stuctures
CH3 CH2 CH2
CH COOH
CH3 CH2 CH2
HOOC
NH 2
-vinyl-GABA
Valproate
H 2NCH 2 CHCH 2 COOH
Baclofen
NH 2 COOH
Gabapentin
O
N
SO2 NH2
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ｾ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.
Davis MDCH 5210 - Anticonvulsants 2006
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Summary of Anticonvulsants - AED’s
A special game for pharmacy students. Based on Letterman’s
“Know Your Current Events”. Also “Know Your Cuts of Meat.”
Know
Know
Know
Know
Know
Know
your
your
your
your
your
your
seizure classes!
seizure inducers (particularly MES, scMET)
mechanisms (Na, Ca, GABA)
main drug structures, know your phenyl rule
benzodiazepines
principles of medicinal chemistry drug design.
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