Anticonvulsant classification, SAR and Individual compounds.

1. Central Nervous System
Depressant
Anticonvulsant
By, Dr. Ganesh S. Andhale,
Alard College of Pharmacy

2. Classification of Anticonvulsant
The various structurally classified anticonvulsant can be
classified as:
1. Barbiturates: Phenobarbitone.
2. Hydantoins : Phenytoin sodium, Ethotoin, Mephenytoin
3. Oxazolidine diones: Trimethadiones, Paramethadone
4. Succinimides: Phensuximides, Methsuximides,
Ethosuximide.
5. Urea and Monoacylureas: Phenacemides,
Carbamazepines.
6. Benzodiazepines: Clonazepams, Diazepam
7. Miscellaneous: Primidones, Valproic acid.

3. General SAR of Anticonvulsant
 Structure common to anticonvulsant drug:
 R”=
 Barbiturate =
 Hydantoins =
N O
O
R
R'
R''
NH
O
N
NH
OO
R
R'
O
NH
N
NH
OO
R
R'

4.  Oxazolidinediones:
 R’’=
 Succinimides:
 R’’=
N O
O
R
R'
R''
O
N
O
OO
R
R'
CH2
N
CH2
OO
R
R'

5.  R & R’’ Should be hydrocarbon radical.
 If Both R and R’ are lower alkyls, the
tendency is to be active against absence
seizures (petit mal) and not active against
generalized tonic-clonic (grand mal) OR
partial seizures.
 If one of the hydrocarbon substituent's is an
aryl group, activity tends to be directed
towards generalized tonic-clonic and partial
seizures and not antiabsence activity.

6. 1. Barbiturate
 Only penobarbital and mephobarbital shows
enough anticonvulsant selectivity.
 The metabolism of Phenobarbital involves
p-hydroxylation, followed by conjugation

7. Phenobarbital
 IUPAC: 5-ethyl-5-phenyl barbituric acid.
 Brand Name: Luminal
 Metabolized to p-hydroxy compound followed
by glucuronide conjugation.
Uses:
1. Sedative
2. Hypnotic
3. Anticonvulsant.
 The anticonvulsant action is mainly due to the
Presence of a phenyl at 5th position.
7

8. 2. Hydantoins
 These are structurally related to
barbiturates but lacking 6-oxo group.
 Hydantoins are more effective as
antigeneralized tonic-clonic rather than
antiabsence activity.
 All the clinically useful generalized tonic-
clonic compounds possess an aryl
substituents on the 5th position
 Hydantoins with lower alkyl substituents
reportedly have antiabsence activity.
N
NH
R"
OO
R
R'

9. 1. Phenytoin:
• IUPAC: 5,5-diphenyl hydantoin.
• It is the prototype drug of
Hydantoin class
• It is prime example of an anticonvulsant
acting as a sodium channel blocker.
• The drug is useful against all seizures
except absence.
• Metabolism proceeds by stereospecific p-
hydroxylation of an aromatic ring followed
by conjugation.
O
HN
NH
O
phenytoin

10. 2. Ethotoin:
• Brand Name: Peganone
• IUPAC: 3-ethyl-5-phenyl-imidazolidine-2,4-
dione
• Metabolism: The N-dealky metabolite, is
the active compound, as well as
metabolized by p-hydroxylation, & then it is
conjugated.
• Used against generalized seizures, on an
adjunctive basis due to its low potency.
O
N
NH
O
H2C
H3C
H

11. 3. Mephenytoin:
• Brand Name: Mesantoin
• IUPAC: 5-ethyl-3methyl -5-phenyl-
hydantoin.
• Metabolism: N-dealkylated to 5-ethyl-5-
phenylhydantoin assumed that active agent.
• Counterpart of phenobarbital.
• Introduced as a sedative-hypnotic and
anticonvulsant as Nirvanol but withdrawn
because of toxicity.
• Activity spectrum similar to phenytoin.
O
N
NH
O
H3C

12. 3. Oxazolidinedione
Eg: Trimethadione, Paramethadione
• Replacement of the N-H group at position 1 of the
hydantoin system with oxygen atoms yield the
oxazolidine-2,4-dione.
• It is having antiabsence activity.
• Aryl substituted oxazolidinedione shown activity
against generalized tonic-clonic seizures but
toxicities may be the problem.
O
HN
O
O

13. 1. Trimethadione:
Brand Name: Tridione
IUPAC: 3,5,5-trimethyl-2,4-oxazolidine
Dione.
Uses: 1st drug introduced specially for treating
absence seizures.
Toxicities: Dermatological & hematological
limits its clinical use.
Metabolism: by N-demethylation to the
dimethadione. Is a calcium-T channel
blocker.
O
N
O
O
H3C
H3C CH3

14. 2. Paramethadione:
IUPAC: 5-ethyl-3,5-dimethyloxazolidine-2,4-
dione.
Uses: Anticonvulsant O
N
O
O
H3C
H3C
H2
C CH3

15. 4. Succinimide
 Eg: Phensuximide, Methsuximide, Ethosuximide
 Is a cyclic imide with the formula C4H5NO2
 Pyrrolidine-2,5-dione
N
CH2
O
O
R
R'
R''

16. 1. Phensuximide:
Brand Name: Milontin
IUPAC:
1-methyl-3-phenylpyrrolidine-2,5-dione
Uses: Used primarily against absence
seizures.
• The phenyl substituent confers some
activity against generalized tonic-clonic
and partial seizures.
Metabolism: N-demethylation to yield active
metabolite then p-hydroxylation.
N
CH2
O
O
H
H3C

17. 2. Methsuximide:
Brand Name: Celontin
• IUPAC:
1,3-dimethyl-3-phenylpyrrolidine-2,5-dione.
• Is found to be effective and potent than
phensuximide.
• Is used against absence and complex
partial seizures.
N
CH2
O
O
H3C
H3C

18. 3. Ethosuximide:
Brand Name: Zarontin
IUPAC:
3-ethyl-3-methylpyrrolidine-2,5-dione.
• It is calcium T channel blocking drug.
• Major metabolite is produced by oxidation
of ethyl group.
• Use:
Conforms very well to the general
structural pattern for antiabsence activity.
N
CH2
O
O
H3C
CH2
H
CH3

19. 5. Urea and Monoacylureas:
Eg: Phenacetamide, Carbamazepine.
Long History of producing compounds with
anticonvulsant activity.
1. Phenacemide:
IUPAC: Phenyl acetyl urea
Use:
• Possess good anticonvulsant activity.
• Less therapeutic value in petit mal, grand mal
and mixed seizures.
H2
C
O
H
N C
O
NH2
phenylacetyl urea

20. 2. Carbamazepine:
Brand Name: Tegretol
• The Two Phenyls substituted on
the urea nitrogen fit the pattern of antigeneralized
tonic activity.
• The overall shape suggest the mode of action,
sodium channel block.
• Use: Generalized tonic-clonic and partial
seizures.
• Toxicity: potential hematological toxicity.
• Metabolism: Proceeds largely through the
epoxide formed at the (Z)cis-stilbine double bond.
Then coverts to the 10s, 11s-trans-diol.
N
O NH2

21. • The epoxide is a suspect in the idiosyncratic
reactions
• thus, oxcarbazepine were developed.

22. 6. Benzodiazepine
Eg: Clonazepam, Diazepam, Chlorazepam.
Detail study regarding Chemistry and
SAR were sees in anxiolytic-sedative-hypnotic
drugs.
Animal models predict that it modestly
effective against generalized tonic-clonic and
partial seizures and very highly active against
absence seizures.

23. 1. Clonazepam
• IUPAC: 5-(2-chlorophenyl)-3-dihydro-7-nitro-2H-
1,4-benzodiazpin-2-one
• Brand Name: Klonopin
• Uses: in absence seizure
• Tolerance often developed
• Metabolism: Hydroxtlation of the 3 position,
followed by glucuronidation.
• Nitro group reduction followed by acetylation.
O
C
N
H
O2N C
Cl
N
CH2

24. 2. Diazepam
IUPAC: 7-chloro-1,3-dihydro-1-methyl
-5-phenyl-1,4-bezodiazepin-2-one.
Brand Name: Valium
 Was the 1st member of the
benzodiazepin-2-one group.
• It is very nonpolar and rapidly absorb.
USES: Anxiolytics in low doses
Antiepileptics
Central muscle relaxant
METABOLISM: By N-demethylation to nordazepam which is
then covert to oxazepam then excreted by glucuronide
conjugation.

25. 7. Miscellanious agents
 Eg: Primidone & Valproic acid.
1. Primidone:
IUPAC: 5-ethyldihydro5-phenyl-
4,6-(1H,5H)-pyrimidinedione
Brand Name: Mysoline.
• Also Called as 2-deoxybarbiturates.
Uses: Against all types of Seizures except
absence.
N
O
C
H2
N
CH2
H
O
H3C
H

26. 2. Valproic Acid
IUPAC: 2-propylpentoic acid
Brand name: Depakene
SAR:
1. Activity increase with increasing chain length.
2. Introduction of double bond decreases the
activity.
3. Introduction of sec. or ter. Hydroxyl group or
replacement of carboxyl by hydroxyl group has
no effect.
MOA:
Act on GABA deactivating Enzyme.
COOH
C
H2
CH2
H2
CH3C
H2
CH3C

27. Metabolism: by conjugation of the
carboxylic acid group and oxidation of the
one of the hydrocarbon chains.
USES:
Active against typical and atypical
absences seizures and absence seizures
with generalized tonic-clonic seizures.