Antiepileptics Medicinal Chemistry

7/30/2019 Antiepileptics Medicinal Chemistry

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Antiepileptic DrugsGisvolds book

Barbiturates

Hydantoins

Oxazolidinedienos

Succinimides

Phenacemides

Glutethemides

Miscellaneous Benzodiazepines


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Mechanism of Actions

Positive allosteric modulation of action of -aminobutyric acid (GABA) at GABAA receptorsite - benzodiazepines and barbiturates

Phenobarbital, may also block voltage gated

Na+-channel

5,5-dialkylbarbiturates, may also block Ca2+

T-channel

Oxazolidine-2,4-diones and succinimides appear

to act via Ca2+ T-channel block

Phenyl-substituted succinimide may also

cause some Na+-channel block

The major mode of action for phenytoin,

carbamazepine, oxacarbazepine, valproic acid,

and felbamate is reported to be voltage-gated

Na+-channel blocker


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Antiepileptic General Structure

C

N

C

C

O

H

O

R1

R2

R3

NH

C

O

NH O CH2 NH2

Barbiturates Hydantions Oxazolidinediones Succinimides Phenacemide

C

C

Glutethimid

O

H2N NH2

Urea

Overall, R1 and R2 should be hydrocarbon

Lower alkyls tend to be active against absence seizures and not active

against generalized tonic-clonic or partial seizures

If one of the hydrocarbon substituent is an aryl group activity tends to be

directed toward generalized tonic-clonic and partial seizures and not

absence seizures


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Barbiturates

NH

N

O

OO

R2

R1 R3

Barbituric acid

First synthesized in 1864 by German researcher Adolf von

Baeyer, the founder of Bayer pharmaceuticals company

by combining urea with malonic acid

The first pharmacologically active compound discovered (1903) was

barbital which was very effective in putting dogs to sleep

Barbital was then marketed by Bayer under the trade name Veronal

(after a peaceful Italian City name) and then Phenobarbital, under the

trade name Luminal, as a sedative-hypnotic

In the 1950s and 1960s, reports began to be published about sideeffects and dependence related to barbiturates

In 1970 several barbiturates were designated as controlled substances

with the passage of the Controlled Substances Act of 1970

Which are under schedules III and IV?


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Barbiturate Structures

The main antiepileptic drug is Phenobarbital major metabolite of which is

the p-hydroxyl and/or the p-hydroxyglucuronide; about 25% excretedunchanged

Mephobarbital is N dealkylated to phenobarbital which many think is theactive drug and thus mephobarbital is a prodrug

N1 and N3 are not distinguishable.

Both drugs being substituted with an aromatic ring at R2 are effective

against generalized tonic-clonic and partial seizures.

R2

H

R3

R1

O

O

ON

N

R1 R2R3

H C2H5 C2H5

H C2H5

CH3 C2H5

H

O

O

SNN

H

N

Barbital

Phenobarbital

Mephobarbital

1

23

4

56

Secobarbital

Thiopental sodiu


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Secobarbital possesses anaesthetic, anticonvulsant, sedative and

hypnotic properties and sometimes used in physician assisted suicides.

The primary metabolites of secobarbital are (-1)-hydroxysecobarbital

(36.5%) and dihydroxydihydrosecobarbital (secodiol, 15.7%), both of

which are excreted also as glucuronide conjugates (26.2%).

Thiopental is an ultra-short-acting barbiturate and has been used

commonly in the induction phase ofgeneral anesthesia and historically to

induce medical comas. It is also used intravenously for the purposes ofeuthanasia. Along with pancuronium bromide and potassium chloride,

thiopental is used in 34 states of the U.S. to execute prisoners by lethal

injection. Thiopental is still used in some places as a truth serum during

interrogation. As with all lipid soluble anaesthetic drugs, the short

duration of its action is almost entirely due to its redistribution away from

central circulation towards muscle and fat tissue. Once redistributed thefree fraction in the blood is metabolized in the liver. Sodium thiopental is

mainly metabolized to pentobarbital.


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Barbiturate Relatives

Primidone is a pyrimidinedione and not abarbiturate but is related where C2 oxidation leads

to conversion into Phenobarbital in vivo which isthought to be the active constituent

Glutethimide is another non barbiturate sedative

hypnotic used as safe alternative to barbiturates

to treat insomnia. It is however a schedule II drug

due to dependency.

N

N

O

O

H3C

H

H

Primidone

2

H3C

O

O

N

H

Glutethimide


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SAR of Barbiturates

Both hydrogen atoms at C5 must be substituted

There is a decrease in onset time and a decrease in duration as C5 alkylchain length increases.

Due to increasing lipid solubility increases rate of CNS penetration for

shorter onset and increases susceptibility to microsomal metabolism due to

penetration into hepatic cells

Common metabolic pathway is and -1 oxidation

Except for those with very high lipid solubility (thiobarbiturates), the

barbiturates have short duration

Thiobarbiturates undergo slow metabolism; most are in the adipose tissue

(depot) and not available to hepatic enzymes which can be converted to

corresponding oxybarbiturate by desulfuration

Bulk on C5(i.e., aromatic ring) is a common feature for drugs with activity forgeneralized seizures and also for partial seizures and status epilepticus, but

not good for absence seizures

N

H

NH

O

O

O


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Hydantoins

N H

NOO

R 2

R 1

R 3

12

34

5

H y d a n to in s

Hydantoin was first isolated in 1881 by Adolf von Baeyer in the course of

his study of uric acid. He obtained it by hydrogenation of Allantoin hencethe name1. Close structural relatives of barbiturates

2. Only lacking the 6-oxo group and are cyclic

monoacylureas rather than diacylureas

3. As a consequence of losing a carbonyl group weaker

organic acids than barbiturates and thus their sodium

salt (e.g., phenytoin sodium) generates stronger alkaline

solution

SAR of Hydantoins

Most of the clinically used drugs in this class possess bulky aromaticring in position C5 that confers usefulness in generalized seizures,

partial seizures and status epilepticus but not well for absence seizures


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Hydantoin Drugs

N

N

O

H

H

O

Phenytoin

H3C

CH3

H

O

O

N

N

Mephenytoin

CH3

H

O

H

O

N

N

Ethotoin

P ONa

ONa

O

O

H

O

O

N

N

Fosphenytoin

Phenytoin is metabolized by p-hydroxylation followedby conjugation similar to Phenobarbital. Mephenytoin

is the hydantoin analogue of mephobarbital which is

also a prodrug, converted into the dealkylated

derivative. Metabolism is also by p-hydroxylation andthen glucuronidation

Ethotoin is dealkylated to the active drug. In this case there is freehydrogen at C5, which explains its very low potency. Metabolism is

also by p-hydroxylation and then glucuronidation

Fosphenytoin is Phosphate ester of phenytoin, rapidly

hydrolyzed to phenytoin in vivo. Phenytoin sodium must bebuffered to an alkaline pH to maintain solubility, thus is

very irritating when injected. Fosphenytoin is neutral

(pH~7) so is less irritating


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Oxazolidinediones

O

NOO

R 2

R 1

R 3

1

23

4

5

O x a z o l i d i n e d i o n e

CH3H3C

H3C O

O

O

N

Trimethadione

H3C

CH3

H3C O

O

O

N

Paramethadione

Replacement of the N-H group at

position 1 of the hydantoin with anoxygen atom yields the oxazolidine-

2,4-dione system

Trimethadione is useful for absence seizures. Note theabsence of bulky substituents at the C5 position which are

useful in absence seizures. It is metabolized to 5,5 dimethyl

oxazolidine 2,4 dione (dimethadione) which is also active. Both

trimethadione and dimethadione are excreted in the urine and

are very toxic

Paramethadione is also N dealkylated, half life is 12-24 hours.

Some excreted by kidney. The metabolite is active and

probably accounts for most activity the half life of which is 14

days and is excreted by the kidney. Also it is fairly toxic


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Succinimides

C H 2

NOO

R 2

R 1

R 3

12

3 4

5

S u c c i n i m id e sSuccinic acid

HO

O

O

OH

H3C

H

H3C

O

O

N

Ethosuccimide

CH3

H3C

O

O

N

Methsuccimide

CH3O

HO

N

Phensuccimide

Ethosuximide is lacking bulky groups attached at C3 which

corresponds to C5 in the other related structures and thus is good

for absence seizures. Major metabolite is from oxidation of the ethylgroup, hydroxyethyl and conjugated hydroxyethyl, both are inactive

This group of drugs resulted from a search

for a less toxic version of the

oxazolidinediones by replacing the Owith CH2

Methsuximide has a bulky group at C3 which is good for absence but

also picks up some partial seizures activity. It is N-dealkylated to an

active metabolite. Half life of methsuximide is 1.4 h, the N demethyl

has a half life of 38 h. So most activity are due to metabolite, followed

by p-hydroxylation and conjugation

Phensuximide possesses the bulky group at C3 which is good for

absence but also picks up some generalized tonic-clonic activity.

Because of the free hydrogen at C3, it is much weaker than the

disubstituted compounds. N-dealkylated to an active metabolite, but

the half life is about the same as the parent (5-12 hr) and the activity is

due to both species. Followed by p-hydroxylation and conjugation


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Miscellaneous

NH2O

N

Carbamazepine Oxacarbazepine

O NH2

O

N

Dibenzazepines structurally related to the

TCAs. The H2NCO function is referred to as acarbamoyl or carboxamide. If the N in the ring

is included we have a urea derivative. So it is

also a ureide

Oxcarbazepine does not undergo such epoxidation so is expected to be less tox


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Valproic Acids

CH3

CH3

OH

O

Valproic acid

H3C

H3C

ONa

O

Valproate sodium

H3C

H3C

ONa

O

CH

CH

HO

O

Divalproexsodium

Discovered accidentally

Valproic acid is a liquid and so is used as a liquid filled capsule

Being an organic solvent not soluble in water for intravenous use.

Valproate sodium was developed as a water soluble salt, but too

hygroscopic for solid oral dosage forms. Also causes GI irritation

and cannot formulate a liquid into sustained release forms

Divalproex sodium is a stable salt for oral tablets and less

irritating to the stomach


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Felbamate is a dicarbamate. Carbamates

are salts or esters of the hypothetical

carbamic acid (H2NCOOH), similar to

meprobamate. But felbamate has a phenyl

(fel-) instead of the methyl, propyl groups

as in meprobamate

NH2

O

O

NH2

O

O

Felbamate

H3C

O

NH2

NH2

H3C O

O

O

Meprobamate

Gabapentin is GABA plus 5 carbons. The idea was to make

GABA more lipid soluble for better CNS penetration. But works

through a non GABA agonist unknown mechanism. Widely

used for neuropathic pain where it is thought to involve voltage-

gated N-type calcium ion channels. The more potent successordrug that is also used to treat neuropathic pain (fibromyalgia) is

pregabalin approved in 2007. Its S-isomer is the active form.

Cl

NH2

COOH

Baclofen

Baclofen modulates mammalian (but not fruit fly) GABAB

receptor. It is used for the treatment of spastic movement,

especially in instances of spinal cord injury, spastic diplegia,multiple sclerosis, amyotrophic lateral sclerosis and trigeminal

and glossopharyngeal neuralgias. It appears to have reduced

abuse and dependence potential. The drug is rapidly absorbed

after oral administration and is widely distributed throughout the

body. Biotransformation is low and the drug is predominantly

excreted in the unchanged form by the kidneys.

O

O H

N H 2

G a b a p e n t in

O

O H

N H 2

P r e g a b a l i n

H


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OH

O

H2N

H2C

VIGABATRIN

Sabril

()-4-amino-5-hexenoic acid

A GABA analog and is dosed as a racemic compound, withthe S-enantiomer being the pharmacologically active form.

The alkene group forms an irreversible, covalent bond with

the gamma-aminobutyric acid transaminase (GABA-T) and

irreversibly inhibits it. The enzyme (GABA-T) is responsible

for the metabolism of the inhibitory neurotransmitter GABA;

its blockade leads to increased levels of GABA in the centralnervous system.

Thus, it is an antiepileptic drug indicated as a monotherapy

for pediatric patients 1 month to 2 years of age with infantile

spasms (IS) and as an adjunctive therapy foradult patients

with refractory complex partial seizures (CPS) who have

inadequately responded to several alternative treatments. It is essentially completely orally absorbed and widely

distributed throughout the body. It is not significantly

metabolized (80% of a dose is recovered as parent drug),

although it does induce CYP2C9, and it is eliminated

primarily through renal excretion.

New Molecular Entity in 2009: Vigabatrin


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FDA denied its approval in February 2010, citing concerns

about possible increased cancer risk shown by some animal

studies. Similar concerns had been raised about gabapentin

itself in the past, but were felt to be outweighed by its

clinical utility as an anticonvulsant, whereas the treatment

of restless legs syndrome was not seen to justify the samekind of risk.

On April 6, 2011, Xenoport received FDA approval for

Horizant (gabapentin enacarbil) for the treatment of

moderate-to-severe restless legs syndrome

New Molecular Entity in 2011

The Benzodiazepines (sedative


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The Benzodiazepines (sedative-hypnotics)

O

N

N

5-Phenyl-1,4-benzodiazepine

A B

C

1

2

54

3

8

9

2'

7

6

1'

4'

3'5'

6'

X

N

N

A B

C

1

2

5

4

3

8

9

2'

76

1'

4'

3'5'

6'

N

10

Annelatedbenzodiazepin

D

Cl

H

OH

Cl

O

N

N

Lorazepam

H

N

O

Cl N

N CH 3

Chlordiazepoxide

C H 3

C l

O

N

N

D iaz ep am

1,4-benzodiazepine-4-oxide

1,4-benzodiazepine-2-oneAnnelated benzodiazepines

N

H 3 C N

N

NC l

A lp r a z o la m

C l

H 3 C

N

N

N

NC l

T r i a z o l a m

Cl N

NO

F

CH3

CH3N

Flurazepam


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OK

COOK

Cl N

N

H

COOK

Cl

O

N

N

KOH

Clorazepate dipotassium

All are basic; most are weakly basic

N4 is basic (imine) in all except for chlordiazepoxide (because the n-

electrons are utilized in forming the N-oxide). The imine is weak because

the carbon atom is attached to two electron withdrawing aromatic rings(ring A and C). e.g., Lorazepam pKa 1.3.

Some are more basic due to substituents at C2 or N1. e.g., chlordizepoxide

the nitrogen substituent at C2 produces an amidine, pKa 4.76; flurazepam

the N1 substituent is a tertiary amine, pKa 8.16.

Some are more basic due to fused ring D. e.g., midazolam the nitrogenspositions 1 an 2 are pyridinelike nitrogen, pKa 6.15

Some are weakly acidic due to the amide (N1C2): The nitrogen must be

unsubstituted to tautomerize. Since amides have a low tendency to

tautomerize, they have a low tendency to ionize, thus are weak acids. e.g.,

lorazepam pKa 11.5

Only one is strongly acidic: clorazepate is the potassium salt of a

carboxylic acid, thus is highly ionized

BDZ Acid-Base Character


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Cl

H

O

O2

N N

N

Clonazepam

N

H

Br

O

N

N

Bromazepam

Cl

O

N

N

CF3

Halazepam

HO

Cl N

N

O

Demoxepam

CH3

Cl N

N

Medazepam

Drug Calc Expt Drug

Calc Expt

Alprazolam 3.87 2.12

Halazepam 3.73 3.97

Bromazepam 1.93 2.05 Lorazepam2.41 2.39

Chlordiazepoxide 2.42 2.44 Medazepam 4.43

4.41

Clonazepam 2.53 2.41 Midazolam

4.33

Clorazepate 2.04 Nordazepam 2.87 2.93

Demoxepam 1.87 1.49 Oxazepam 3.32 2.24

Diazepam 2.7 2.82 Prazepam 3.99 3.73

Estazolam 3.32 Quazepam 4.3 4.03

Flumazenil 1.03 1.0 Temazepam 2.15

2.19

Flunitrazepam 1.91 2.06 Triazolam 3.96

2.42

Flurazepam 3.02

from http://esc.syrres.com


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Currently there are only four drugs available in injectable form only oneis in pure aqueous solution

The other three utilized organic co-solvents which are irritating to tissue

Two factors are responsible; the low water solubility and the

susceptibility of ring B to hydrolysis. Benzodiazepines in solution exist

in equilibrium with the inactive benzophenone analog produced by theopening of the N4-C5 double bond (a Shiff base). Low pHs favor the

benzophenone structure, which also favor aqueous solubility. In this

form the amide is susceptible to hydrolysis. Recall that low pHs catalyze

hydrolysis. Thus benzodiazepines are unstable in acid pHs. Fortunately

at blood pH of 7.4 benzodiazepines exists in the closed ring B form.

BDZ Metabolism ????

N

N

O

Cl

CH3N

NH2

O

Cl

CH3

O

N

Cl

CH3

O

H

NH2

O

HO

Diazepam

Cl N

N

NCH3

F

Cl NH2

N

NCH3

F

O

Midazolam


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BDZ SARs

5

4

3

2

1

lipophilicp ock et

lipophilicsite

lipophilisite

N

N

O

Cl

CH3

Diazepam

2

3

4

Chlordiazepoxi

N

N

H

N

Cl

O

CH3

1) Applicable to 4-oxides only

a) nitrogen at position 2 is not essential (does increase basic character)

b) increasing size of 2 substituent beyond methyl decreases potency. Thisgroup can not bind with Site 2 and may introduce steric hindrance.

c) the N-oxide is not essential and decreases potency. Since it is a polar

group it has a repulsive interaction with site 4.

2) Ring A SARs

a) Small e/w substituents at C7 increase potency: NO2 > CF3 > Br > Cl > H >phenyl

b) Substituents on other ring A positions decrease potency. e/w groups

make ring A slightly electron deficient. This increase the London interaction

with Site 1. Groups at other positions have the same electronic effects.

c) Large groups or electron donors decrease potency. These introduce steric

factors. Clonazepam with a 7-nitro has an IC50 of 1.8.

IC50 = 1.8 IC50 = 350

Cl

H

O

O2

N N

N

Clonazepam


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a) Removal of phenyl at C5 decreases potency

b) Replacement of phenyl with isostere at C5 is allowed. Ring C provides a

London interaction with Site 5. Loss activity if this interaction decreases binding

with the receptor

c) Isosteric replacement of O by S at C2 decreases potency. Generally this

isosteric replacement results in an increase in potency. However, since the

benzodiazepeines are so lipid soluble, the increase in lipid solubility makes the

log P too high

d) Saturation of atoms at 4 and 5 form sp2 hybridized to sp3. This changes the

shape of ring B. Further studies have shown that the shape of ring B is the most

important factor determining binding. Dihydrodiazepam has an IC50 greater than

1000 vs 8.1 for diazepam.

N

N

O

Cl

H

OH

N

N

O

Cl

CF 3

N

N

O

Cl

H

Nordazepam Halazepam Oxazepam

3) Ring B SARs

5

4

3

2

1

lipophilicpock et

lipophilicsite

lipophilisite

N

N

O

Cl

CH3

Diazepam

2

3

4


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e) A methyl is the best substituent at N1.

1) By removing the methyl the interaction with Site 1 is lost. (nordiazepam)

2) Increasing the size of the alkyl introduces steric factor, however linear

substituents retain sufficient potency to be useful clinically, but bulky

groups like t-butyl produce very weak agents.

f) A hydroxyl at C3 decreases potency as polar group interacting with the

lipophilic Site 3, decrease half-life, as it is susceptible to rapid

glucuronidation. The decrease in toxicity is due to the ease of metabolism

(oxazepam).

g) Annulation with triazole or imidazole markedly increases potency. The

ring increases LWPC and increases receptor affinity. Annelated

benzodiazepines are more potent than corresponding 2-one derivatives.

N

N

O

Cl

H

OH

N

N

O

Cl

CF 3

N

N

O

Cl

H

Nordazepam Halazepam OxazepamIC50 of 8.4

(8.1 for diazepam)IC50 of 92

(14.8 for flurazepam)IC50 of 18

(14.8 for flurazepam)

Cl N

NO

F

CH3

CH3N

Flurazepam


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4) Ring C SARs

a) Halogenation only at 2' enhances potency, other positions

decrease potency: Cl > F > Br > NO2 > CF3 > H. Electron withdrawinggroups have similar electronic effects as discussed for ring A, thus

promote binding with site 5. (Lorazepam)

5) 1,2-Annelated SARs

a) Introduction of 1methyl shortens duration of action. The 1-methyl

is very susceptible to oxidation, thus easily hydroxylated. Thehydroxy metabolite retains potency but may be quickly conjugated

and excreted.

Cl

H

OH

Cl

O

N

N

Lorazepam

IC50 3.5

18 for oxazepam

N

H 3 C N

N

NC l

A lp r a zo la m

C l

H 3 C

N

N

N

NC l

T r i a z o l a m


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New Drugs in 2011

Clobazam is approved in October 2011 as an

antiepileptic agent. It is available in oral form only,

due to its insolubility in water. It has been in the

clinic formany years for its anticonvulsant andanxiolytic actions.


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BDZ Mechanism of Action

As with the barbs, the GABAA receptor complex is implicated as the site of

action. The GABAA receptor is a ligand gated ion channel composed of

different combinations of, , , subunits.16, 13, 13,, 13. Different combinations result in affinity for different

drugs and producing different activities

Major subtype (60% ): 122: Sedative, amnestic, anticonvulsant

Minor subtype (15% ): 232: Anxiolytic

Minor subtype (10% ): 3n2

To date three BDZ receptors have been identified. The BDZ receptors are

also known as omega1, omega2 and omega3. The BDZ1 receptors are

located in areas of the brain that are involved in sedation, and the BDZ2

receptors are highly concentrated in areas responsible for cognition,memory, and psychomotorfunctioning. The BDZ3 receptors are located

in peripheral tissues and not involved in hypnotic efficacy. The BDZs bind

to all three receptor subtypes. This lack of selectivity allows the

benzodiazepines to be used as anticonvulsants, sedatives, hypnotics,

anxiolytics muscle relaxants and general anesthetics, the activity is

determined by the dose and the desires of the company.

Other Benzodiazepine Receptor Ligands: Type 1 selective agents should have less


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Other Benzodiazepine Receptor Ligands: Type 1 selective agents should have less

central adverse effects on cognition, memory, and psychomotor function.

Compared to benzodiazepine, these agents have little effect on the normal

stages of sleep, and few if any anxiolytic, anticonvulsant, muscle relaxant

properties or amnesia.

Zolpidem, Zaleplon and Eszopiclone selectively bind to BDZ1 receptors.Hypnotic efficacy may not differ between benzodiazepine and the newer

selective agents. Zaleplon has a half-life of 1 hour. This allows dosing up to four

hours before a patient needs to be awake. However, it may lead to awakening

during the night. Eszopiclone has the advantage of being the only hypnotic

approved by the FDA for continual use.

O

CH3

O

F

CH3O

N

N

N

Flumazenil

Benzodiazepine Receptor Antagonists

Benzodiazepine antagonists are useful in treating

overdoses and in terminating benzodiazepine

induced anesthesia. Flumazenil binds the receptor

with high affinity (IC50 2.5) but the lack of ring C and

the modifications of ring B prevent activation of the

receptor. Activity is terminated by hydrolysis to theinactive acid.

O

CH3

CH3N

H3C

CH3

N

N

Zolpedem O

CH3

CH3

N

C

N

N

N

N

Zaleplon

Cl

CH3NN

O

O

O

N

N

N

N

Eszopiclone


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Case 1. JB, a 34-year-old woman, was the recent victim of car accident in

which she sustained a severe head injury. She has come to emergency

room after suffering a severe, generalized tonic-clonic convulsive

episode. She is hospitalized and, within the next few days, two more

generalized seizures are experienced. It is decided to initiate chronic

anticonvulsant therapy, and your advice is solicited.

Case Study

CH3

H3C

H3C O

O

O

N

1N

N

O

H

H

O

2

H3C

H

H3C

O

O

N

3

H3C

CH3

H

O

O

N

N

4

N

N

O

O

O

H3C

H

H

5

1. Which of the anticonvulsant structures (1-5) should beadministered to JB?

2. What structural features of your drug of choice are

responsible for your answer?

S G


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Study Guide

The mode of action of all antiepileptic drugs

Critically analyze the differences in structural changes of all theclasses. How the bulkiness of groups R1 and R2 affect the activity of

the drugs against generalized seizures, partial seizures or absence

seizures?

Structures of most important drugs in these classes in the way that

you can recognize them

Metabolic pathways and pharmacokinetics of the drugs indicated

SAR in general and also for the individual drugs

SAR of BDZs. What is truth serum? Which drugs are used to cause

physician assisted suicide or execute the criminals? Know all about vegabatrin

Which antiepileptic class of drugs are most toxic?

Which receptor(s) are modulated by BDZs?

Which ones are Type-1 selective agents? What are their advantages?

Antiepileptics Medicinal Chemistry

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