M pharm pharmaceutical Chemistry sem 1 Advance Medicinal chemistry

1. Medicinal chemistry of Anticonvulsant
drug
Presented by, Guided by’
Nikita Borade Dr. Prof.Mrs.Merekar
M pharm (Pharmaceutical chemistry PDVVPF’S college of
1st year Pharmacy , A.nagar
Sub: Advance Medicinal Chemistry
Topic: Anticonvulsant drug
PDVVPF’S college of pharmacy ,A.nagar

2. Introduction
 Convulsion: A condition in which muscles contract and relax quickly and cause
uncontrolled shaking of the body.
 Head injuries, high fevers, some medical disorders, and certain drugs can cause convulsions.
They may also occur during seizures caused by epilepsy.
 A type of drug that is used to prevent or treat seizures or convulsions by controlling abnormal
electrical activity in the brain.
 Anticonvulsants are used to treat epilepsy and other seizure disorders.
 Epilepsy is a CNS disorder in which brain activity becomes abnormal, causing seizures or
period of unusual behavior.
 Epilepsy is a long term chronic disease.

3. Types of Epilepsy :
Partial Generalize
Simple Partial Absence seizures
Complex Partial Tonic seizures
Atonic seizures
Clonic seizures
Myoclonic seizures

4.  Partial Seizures : The abnormal electric Surge happens within a limited area of the brain. Also
called as focal seizures.
 Simple Partial: Depending on the affected brain area, patient may have unusual feelings or
uncontrollable jerking movements.
 In simple partial seizures patient remains conscious and aware of the surrounding.
 Complex Partial: involve a loss or change in consciousness.
 Generalize seizures : Entire brain is involved.
 Absence seizures : most often in children. Characterized by brief loss of awareness.
( blank staring ).
 Tonic seizures : associated with stiffening of muscles or increase muscle tone.
 Atonic seizures: Also known as drop attacks, characterized by a sudden loss of muscle tone.
Person may collapse or drop down.
 Clonic seizures: associated with rhythmic jerking muscle movements. Most common affected
areas are neck, face, arms and legs
 Myoclonic seizures are sudden brief jerks of muscles.
 Tonic Clonic seizures: also known as convulsive seizures. These are combination of muscles
stiffing and jerking. Also involve loss of consciousness and sometimes loss of bladder control.

5. Drugs used in epilepsy:
 Barbiturates: Phenobarbital, Mephobarbital.
 Hydantoin Derivatives: Phenytoin, Phenylethyl Hydantoin.
 Oxazolidinedione derivatives : trimethadione, paramethadione.
 Succinimides: Phensuximide, Methsuximide
 Benzodiazepine: Diazepam, Clonazepam
 GABA Analogues: progabide, tiagabine.

6. Mode of actions.
Barbiturates:
 barbiturates potentiate the effect of GABA at the GABA- A receptor.
 The GABA-A receptor is a ligand gated ion channel membrane receptor that allows
for the flow of Cl through the membrane in neurons.
 GABA is the principle neurotransmitter for this receptor which upon binding causes
the channel to open and creates a negative charge in the transmembrane potential.
 This makes it an Inhibitory neurotransmitter.

7. Hydantoin
 Prolongs inactivated stage of Na+- channels
 Increases refractory period of neurons.
 Selectively inhibits the high frequency discharges implicated in epilepsy.
 No effect on normal synaptic transmission.
Oxazolidinedione
 Block the voltage gated Calcium channel.

8. Succinimide
 Block the voltage gated calcium channel at post synaptic cleft.
 There by prevent the excess firing of excitatory calcium ions in the synaptic cleft.
 No effect on normal synaptic transmission.

9. Benzodiazepine:
 Benzodiazepines work by increasing the efficiency of a natural brain chemical,
GABA, to decrease the excitability of neurons.
 GABA controls the excitability of neurons by binding to the GABA receptor. The
GABA A receptor located in the synapses of neurons.
 All GABA receptors contain an ion channel that conducts chloride ions across
neuronal cell membranes and two binding sites for the GABA, GABA receptor
complexes also contain a single binding site for benzodiazepines.
 Binding of BDZ to this receptor complex promotes binding of GABA, which in turn
increases the conduction of chloride ions across the neuronal cell membrane.
resulting in inhibition of neuronal firing.

10. GABA Analogue:
 Activation of GABA A receptor.
Opening of central pores
Influx of Cl- ions through the pore
Hyperpolarization of the neuronal membrane.
Occurrence of action potential
Inhibition of neurotransmission

11. Structural activity relationship benzodiazepines.
 The electron withdrawing atom or group at position 7 increases the anti-epileptic
activity while electron donating substituents at 7, 8 or 9 positions decrease it.
 R2A phenyl group at position 5 is necessary for activity. But only halogen
substituents are allowed in the ortho position.
 The electron withdrawing groups at ortho or diortho positions at 5-phenyl increase
the activity while any substituents on meta or para position at 5-phenyl decreases
the activity.
 R2Methyl substitution at position 1 confirms high activity.

12.  Structure of diazepam Clonazepam

13. Hydantoin

14.  Structure of phenytoin phenylethyl hydantoin

15. Succinimide
 Methsuximide and phensuximide have phenyl substituents which makes them active against
electrically induced convulsion.
 ON-Methylation decreases activity against electroshock seizures and impart more activity
against chemically induced convulsion.

16.  Structure of Methsuximide phensuximide

17. Barbiturates
 Optimum activity is observed when one of the substituents at C5 is phenyl.
 The 5, 5-diphenyl derivatives have less activity than phenobarbitone.
 N2 and N3 substituents, in some cases also results in an increased activity.
 Barbiturates 5, 5-dibenzyl barbituric acid causes convulsions.

18.  Structure of phenobarbital Mephobarbital

19. Synthesis
 Phenobarbital:

20. Phenytoin

21. Diazepam

22. progabide

23. Thankyou…