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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
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Classification of Seizures
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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 dont 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
Davis MDCH 5210 - Anticonvulsants 2006
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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Davis MDCH 5210 - Anticonvulsants 2006
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 NH
[ox]
O HN O NH
O H2N
O NH 2
phenylethylmalondiamide PEMA
Primidone
Phenobarbital
CH2 CH3
Phenytoin (Dilantin)
11
SAR-2
N CH 3
Ethosuximide (Zarontin)
Benzodiazepines Clonazepam and Clorazepate are good for scMET induced seizures, not so good for MES seizures. Diazepam is used for status epilepticus.
H N O2N N Cl O H N Cl N CH 3 N COO K
+
Cl
Clonazepam
Clorazepate
Diazepam
Davis MDCH 5210 - Anticonvulsants 2006
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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.
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Davis MDCH 5210 - Anticonvulsants 2006
Structures
Cl Cl N H2 N O H2 N N N
N NH2
Carbamazepine
Lamotrigine
O O O O
S N CH3 S CH 3
O OH
Topiramate (Topamax)
Tiagabine (Gabitril)
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Davis MDCH 5210 - Anticonvulsants 2006
More Stuctures
CH COOH HOOC NH 2
Valproate
H 2NCH 2 CHCH 2 COOH
-vinyl-GABA
NH 2 COOH
Baclofen
Gabapentin
O N
SO2 NH2
Zonisamide (Zonegran)
Davis MDCH 5210 - Anticonvulsants 2006
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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 Nrum, 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
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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.
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Summary of Anticonvulsants - AEDs A special game for pharmacy students. Based on Lettermans Know Your Current Events. Also Know Your Cuts of Meat.
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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Davis MDCH 5210 - Anticonvulsants 2006