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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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Strychnine ² blocks glycine receptors


Bicuculline ² GABA antagonist
Picrotoxin ² Blocks GABA Cl- ion channels

Maximal electroshock (MES)


Pentylene tetrazole (sc MET)

 

 
  

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.

  
 


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Mechanisms


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Na and Ca Channels

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MES Seizures
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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.

 




  Alter Na+ and K+ ion conductances, interact
with ion channels in membranes. Some have a similar mechanism of action to local
anesthetics.

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Phenyl ring(s) are necessary (first group). Example is phenobarbital. Valproate is an


exception because it works for everything.

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Carbamazepine
Phenytoin
Phenobarbital
Primidone
Valproate

Gabapentin
Lamotrigine
Zonisamide
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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.

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Ethosuximide
Clonazepam
Valproate
Lamotrigine?

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Seizures and Drugs.

  
 



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  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.
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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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›  ! ² Ineffective against Met induced seizures, but is
good for mixed seizure patients in the partial group. Na+ channels.

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·  ! ² Na+ channels. Similar to phenytoin and carbamazepine.

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|  # ! ² Broadest activity of all antiepileptic agents. Affect Na+ channel
recovery and also increases GABA levels. May stimulate synthesis or inhibit degradation.

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%   ! ² Promotes GABA release. Was supposed to be a GABA agonist,
but it doesn·t work that way. Baclofen may also work that way.

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 ! ² Inhibits GABA transaminase. There are a number
of compounds that do this.

  
  &! - 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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- GABA reuptake inhibitor. Interesting SAR

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'  ! - Na+ channels or Ca+2 channels.



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Zonisamide (Zonegran)


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MedChem/Drug Design

  

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u +Lars J. S. Knutsen,
Knud Erik Andersen, Jesper Lau, Behrend F. Lundt, Rodger F. Henry, Howard E. Morton, Lars
N6rum, Hans Petersen, Henrik Stephensen, Peter D. Suzdak, Michael D. B. Swedberg,
Christian Thomsen, and Per O. Srensen
J. Med. Chem.; +,,,- ‰ (18) pp 3‰‰ - 3‰ ;


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MedChem/Drug Design-2

Model for SAR of GABA Reuptake Inhibitors.

The ´linkerµ 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 ++, +, and +*. 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 + has a less electronegative region in the linker than the vinyl ether +*; both are
significantly different from the pentenyl analogue ++ 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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