antiepileptics medicinal chemistry
TRANSCRIPT
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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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7/30/2019 Antiepileptics Medicinal Chemistry
30/30
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?