Anticonvulsants 2006

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Davis MDCH 5210 - Anticonvulsants 20061

Selective CNS drugs (Depressants), used to treat epilepsy. These syndromes affectabout 1% of the population.

One would hope to have anticonvulsants that affect pathologically altered neurons ofseizure foci, which would then prevent or reduce their excessive discharge.

The way that anticonvulsants work is to reduce the spread of excitation from seizurefoci 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 andspreads throughout the brain. The pattern of initiation and the extent of propagationdetermines the type and severity of the seizure.

Anticonvulsants


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Anticonvulsant tests:

Strychnine blocks glycine receptorsBicuculline GABA antagonistPicrotoxin Blocks GABA Cl- ion channels

Maximal electroshock (MES)Pentylene tetrazole (sc MET)

Two Major Seizure classes

PartialGeneralized Absence

Note: Generalized tonic-clonic seizures respond to the same drugs aspartial seizures.

Anticonvulsant tests - Major Seizure classes :


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Classification of Seizures


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Valproate

Lamotrigine

Seizures and Drugs.


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Mechanisms


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GABA


7/19Davis MDCH 5210 - Anticonvulsants 20067

Na and Ca Channels



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, interactwith ion channels in membranes. Some have a similar mechanism of action to localanesthetics.

SAR of partial seizure/MES compounds:Phenyl ring(s) are necessary (first group). Example is phenobarbital. Valproate is anexception because it works for everything.

Drugs:CarbamazepinePhenytoin

PhenobarbitalPrimidoneValproate

GabapentinLamotrigineZonisamide

MES 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:EthosuximideClonazepamValproateLamotrigine?

Drugs effective against scMET seizures:



Valproate

Lamotrigine

Seizures and Drugs.



Barbiturates and related compounds.- Phenobarbital has been widely used. Otherbarbiturates have no advantages, but the phenyl-substituted barbiturates are effective.

SAR is the same as for sedative/hypnotic effects.

HN NH

OO

HN NH

OO

O

[ox]

H2N NH2

OO

Primidone Phenobarbital

phenylethylmalondiamide

PEMA

Hydantoins. Na+ channels

N

N

O O

H

H

Ph

Ph

N

N

O O

H

CH2CH3

PhH

Phenytoin (Dilantin) Ethotoin

"less effective than phenytoin

SAR-



Succinimides. Ca+2 channels

NO O

H

CH3

H3C

Ethosuximide (Zarontin)

NO O

CH3

CH3

Phensuximide(Not as good, but is anticonvulsan

Benzodiazepines

Clonazepam and Clorazepate are good for scMET induced seizures, not so good for MESseizures. Diazepam is used for status epilepticus.

N

N

Cl

OCH3

N

N

Cl

OH

COO-K+

N

N

O2N

O

Cl

H

Clonazepam Clorazepate Diazepam

SAR-2



Carbamazepine (Tegretol, Carbatrol) Ineffective against Met induced seizures, but isgood 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+ channelrecovery 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 doesnt work that way. Baclofen may also work that way.

-vinyl GABA (vigabatrin), (Sabril). Inhibits GABA transaminase. There are a numberof 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.

Tiagabine (Gabitril) - GABA reuptake inhibitor. Interesting SAR

Zonisamide (Zonegran) - Na+ channels or Ca+2 channels.

Miscellaneous/Important mechanisms of action:



N

H2N O N

NN

ClCl

NH2H2N

Carbamazepine Lamotrigine

O CH2OSO2NH2

O

OO

O

N OH

S

CH3S

CH3

O

Topiramate (Topamax) Tiagabine (Gabitril)

Structures



CH COOH

CH3CH2CH2

CH3CH2CH2NH2HOOC

H2NCH2CHCH2COOHNH2 COOH

Valproate -vinyl-GABA

Baclofen Gabapentin

N

O

SO2NH2

Zonisamide (Zonegran)

More Stuctures



Synthesis of Novel GABA Uptake Inhibitors. 3. Diaryloxime and Diarylvinyl EtherDerivatives 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, LarsNrum, Hans Petersen, Henrik Stephensen, Peter D. Suzdak, Michael D. B. Swedberg,Christian Thomsen, and Per O. SrensenJ. Med. Chem.; 1999;42(18) pp 3447 - 3462;

MedChem/Drug Design



Model for SAR of GABA Reuptake Inhibitors.

The linker region has been proposed to interact with a positive regionof the GABA transporter.

MedChem/Drug Design-2



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Electrostatic potential calculations52 for molecules 11, 12, and 13. The most electronegative surface is represented by the redshading (the linker is indicated by the red arrows), graduating toward the electropositive via yellow and green to blue as the mostelectropositive. As proposed, the oxime 12 has a less electronegative region in the linker than the vinyl ether 13; both aresignificantly different from the pentenyl analogue 11 of tiagabine. This is reflected in their activities as inhibitors of [3H]-GABAuptake in vitro, which are 335, 41, and 14 nM, respectively.

MedChem/DrugDesign-3


19/19D i MDCH 5210 A ti l t 2006

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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 ruleKnow your benzodiazepinesKnow your principles of medicinal chemistry drug design.

Summary of Anticonvulsants - AEDs
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Anticonvulsants 2006

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