Davis MDCH 5210 - Anticonvulsants 2006 1 Selective CNS drugs (Depressants), used to treat epilepsy....

Davis MDCH 5210 - Anticonvulsants 2006

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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.

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 as partial seizures.

Anticonvulsant tests - Major Seizure classes :


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Classification of Seizures


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ValproateLamotrigine

Seizures and Drugs.


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Mechanisms


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GABA


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Na and Ca Channels


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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:CarbamazepinePhenytoinPhenobarbitalPrimidoneValproate

GabapentinLamotrigineZonisamide

MES Seizures


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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.

Drugs:EthosuximideClonazepamValproateLamotrigine?

Drugs effective against scMET seizures:


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ValproateLamotrigine

Seizures and Drugs.


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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.

HN NH

OO

HN NH

OO

O

[ox]

H2

N NH2

OO

Primidone Phenobarbital

phenylethylmalondiamide

PEMA

Hydantoins. Na+ channels

N

N

OO

H

H

Ph

Ph

N

N

OO

H

CH2

CH3

Ph

H

Phenytoin (Dilantin)Ethotoin

"less effective than phenytoin"

SAR-


12

Succinimides. Ca+2 channels

NOO

H

CH3

H3

C

Ethosuximide (Zarontin)

NOO

CH3

CH3

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.

N

N

Cl

O

CH3

N

N

Cl

O

H

COO

-

K

+

N

N

O2

N

O

Cl

H

ClonazepamClorazepate Diazepam

SAR-2


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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 non-NMDA glutamate receptors.

Tiagabine (Gabitril) - GABA reuptake inhibitor. Interesting SAR

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

Miscellaneous/Important mechanisms of action:


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N

H2

N ON

N

N

Cl

Cl

NH2

H2

N

CarbamazepineLamotrigine

OCH

2OSO

2NH

2

O

OO

O

N OH

S

CH3

S

CH3

O

Topiramate (Topamax)Tiagabine (Gabitril)

Structures


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CH COOH

CH

3

CH

2

CH

2

CH

3

CH

2

CH

2

NH

2

HOOC

H

2

NCH

2

CHCH

2

COOH

NH

2

COOH

Valproate

- -vinyl GABA

Baclofen

Gabapentin

N

O

SO2NH2

Zonisamide (Zonegran)

More Stuctures


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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. SrensenJ. Med. Chem.; 1999; 42(18) pp 3447 - 3462;

MedChem/Drug Design


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Model for SAR of GABA Reuptake Inhibitors.

The “linker” region has been proposed to interact with a positive region of 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 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.

MedChem/Drug Design-3


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A special game for pharmacy students. - Based on Letterman’s “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 - AED’s

Davis MDCH 5210 - Anticonvulsants 2006 1 Selective CNS drugs (Depressants), used to treat epilepsy....

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