Dr.Narmin hamaamin Hussen

1. Barbiturates
Dr.Narmin Hamaamin Hussen
College of pharmacy/University of Sulaimani
Medicinal chemistry III / 4th stage/ 1st semester
Lecture 2
2023-2024
Phenobarbital
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2. Barbiturates
▪Drugs that depress the activity of the central nervous system, reducing anxiety,
insomnia and seizure disorders
▪They are effective as anxiolytics, hypnotics, anticonvulsants and analgesics
▪ They enhance the action of GABA, a neurotransmitter that inhibits the activity of
nerve cells in the brain
▪They are not commonly prescribed these days, having been largely superseded
by benzodiazepines, which are much safer
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3. History of Barbiturates
▪Barbituric acid was first synthesized 27 November
1864, by German chemist Adolf von Baeyer, but the
first pharmacologically active agent, barbital, was not
produced until 1881 and introduced to medicine in
1904
▪He received the Nobel Prize for Chemistry in 1905
for the results of his work in the field of organic dyes
and hydroaromatic compounds.
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4. Mechanism of Action
▪Unlike benzodiazepines, they bind at different
binding sites and appear to increase the duration
of the GABA-gated chloride channel openings.
▪Increases the duration of chloride flow through
the open channel. While benzodiazepines
increase frequency
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5. Barbiturate General Structure and Numbering
▪ Barbituric acid is the parent compound of barbiturate drugs.
▪ The barbiturates are 5,5-disubstituted barbituric acids.
▪ Barbiturates are cyclic ureides which are the derivatives of
barbituric acid (2,4,6-trioxohexahydropyrimidine).
▪ All barbiturates are derivatives of barbituric acid (2,4,6-
trioxyhexahydropyrimidine).
▪ Barbituric acid itself does not possess any hypnotic properties.
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6. Synthesis Barbituric acid
▪ Barbituric acid may be described as a "cyclic ureide of malonic acid.
▪The synthesis of barbituric acid is effected by condensation of diethyl malonate
with urea in the presence of sodium ethoxide which may be prepared by
reacting Na metal with ethanol and it undergo cyclization reaction with diethyl
malonate.
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7. Structure–Activity Relationships of Barbiturates
1st position , 3rd position and 5th position
➢ Activity requires a balance of acidic and lipophilic properties.
▪ To make the drug sufficiently acidic, both or at least one of the two nitrogen must be
unsubstituted .
▪ To make drug sufficiently lipophilic, the two hydrogen atoms at position 5 : 5 must
have the appropriate substituent (e.g., alkyl or aryl groups) .
The type of substituent's control 2 aspects of the drug:
✓ Potency
✓ Duration of Action.
Barbituric acid
No 5-substituents
Inactive
because not lipophilic
enough
Acidity (pKa) 4.01
5-substituted
Inactive
because not lipophilic enough
1,5-Disubstituted
Inactive
because not lipophilic enough
N-1, N-3
Disubstituted
Inactive
(Non-acidic!!!!)
5,5-Disubstituted
Barbiturate
Active
weak acids (pKa about 8)
1,5,5-trisubstituted
Active
1,3,5,5-tetrasubstituted
Inactive
(Non-acidic!!!!)
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8. Acidity of barbiturates
1st position and 3rd position
▪ The acidity value within certain limits to give proper ratio of ionized (dissociated) and
unionized forms, which is important to cross blood brain barrier (BBB).
▪ It takes approximately 40%–60% dissociation to enable a barbiturate to cross BBB and
exert effects on CNS. Determination of the pKa can thus be predictive of the CNS activity.
▪ The relative acidity of different barbiturates is a function of the degree of N-substitution
and C-5-substitution as shown below:
Barbituric acid easily undergoes
ionization at plasma pH 7.4 , due
to which , it cannot cross BBB and
hence pharmacologically
inactive
5,5-disubstituted and 1,5,5-trisubstituted Barbituric acids are present
in unionized forms at plasma PH because of their high PKa values
which can easily cross BBB and hence pharmacologically active
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9. ▪ Methylation of one of the imide hydrogens enhances onset of action
1st position
Methylphenobarbital
Methylation
position1
pKa= 7.4 pKa= 8
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10. 2nd position (thiobarbiturates)
▪ Replacement of C-2 O by S → ↑ lipid solubility.
▪ Thiopental (Pentothal) and thiamylal (Surital) are called thiobarbiturates because they
possess a sulfa molecule and are quite similar pharmacologically.
▪ Thiopental used as IV anesthetics due to rapid onset & quick brain levels achieved.
• Thiamylal used as IV administration, the onset of action of these drugs is rapid (within
30 to 40 seconds) and of short duration.
▪ Introduction of more sulfur atoms (2,4-dithio derivatives) destroys potency, due to decreased hydrophilic character
beyond required limits.
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11. Lipophilicity of barbiturates
➢ In general, increasing lipophilicity, increases hypnotic potency and the onset of action and decreases the duration of
action.
The number of carbon atom at C-5
▪ Side chains at position 5 are essential for activity .
▪ The total number of carbon atoms present in the two groups at carbon 5 must not be less than 4 and more than 10 and
influences onset of action and duration.
▪ Sedative and hypnotic activity increases with lipid solubility until the total number of carbon atoms of both substituents at
C-5 is between 6 and 10.
▪ Long chains are readily oxidized and thus produce short-acting barbiturates.
➢ Example: Secobarbital, Pentobarbital (Secobarbital contains total 8 carbons at C-5, where as Pentobarbital contains
total 7 carbons. Hence, secobarbital is more active than Pentobarbital)
▪ Short chains at carbon 5 resist oxidation and hence are long-acting. Example: Barbital
Total carbon Duration of action
7-9 Rapid onset and shorter
duration
5-7 Intermediate duration of
action
4 Slowest onset and longest
duration of action( two
ethyl group) e.g. Barbital
5th position:
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12. 5th position:
Branched chain isomer:
▪ Within the same series, the branched chain isomer has greater lipid solubility and activity,
and shorter onset of action than the straight chain isomer.
▪ The greater the branching, the more potent is the drug (e.g., pentobarbital >
amobarbital).
Log P = 2.10
Pentobarbital Amobarbital
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13. Alkyl or Aryl substitution at position 5:
▪ Presence of an alkyl or aryl substitution at position 5 confers sedative –
hypnotic and anticonvulsant properties .
▪ Barbiturate with single 5-phenyl substituent have selective anticonvulsant
activity.
▪ Ex: Phenobarbital ( 5-phenyl-5-ethylbarbituric acid).
▪ The 5,5-diphenyl derivative has less antiseizure potency than does
phenobarbital and is virtually devoid of hypnotic activity.
▪ Aromatic and alicyclic moieties exert greater potency than the
corresponding aliphatic moiety having the same number of carbon
atoms
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14. ▪ Double bonds in the alkyl substituent groups produce compounds more readily vulnerable
to tissue oxidation ; hence, they are short-acting.
Double bonds or unsaturated alkyl groups :
Short Duration of Action (Less Than 3 Hours)
Short-acting, and has a rapid onset of action
IV: 2 to 10 minutes
✓ Introduction of a halogen atom into the 5-alkyl substituent ↑ the potency.
✓ Inclusion of polar groups (e.g., OH, CO, COOH, NH2, RNH, and SO3H) in the 5-alkyl moiety reduces
potency considerably.
5th position:
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15. Classification of Barbiturates
Barbiturates are classified according to their duration of action into:
1. Long duration of action (> 6 hours).
2. Intermediate duration of action (3-6 hours).
3. Short duration of action (< 3 hours)
4. Ultrashort duration of action (intravenous anesthetics)
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16. Barbiturates with a Long Duration of Action (More Than 6 Hours):
1-Mephobarbital.
▪ Mephobarbital, 3-methyl-5- ethyl-5-phenylbarbituric acid (metharbital), is metabolically N-
demethylated to phenobarbital, which many consider to account for almost all of the activity.
▪ Its principal use is as an anticonvulsant.
2- Phenobarbital.
▪ Phenobarbital, 5-ethyl-5-phenylbarbituric acid (Luminal), is a long-acting sedative and
hypnotic.
▪ It is also a valuable anticonvulsant; especially in generalized tonic–clonic and partial
seizures.
▪ Metabolism to the p.hydroxylphenyl compound followed by glucuronidation accounts for
about 90% of a dose.
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17. Barbiturates with an Intermediate Duration of Action (3–6 Hours):
1- Amobarbital, 5-ethyl-5-isopentylbarbituric acid (Amytal), and its water-soluble sodium salt.
2- Butabarbital sodium, is water-soluble sodium salt of 5-sec-butyl-5-ethylbarbituric acid
(Butisol Sodium).
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18. Barbiturates with a Short Duration of Action (Less Than 3 Hours):
Log P= 2.33
Log P= 2.10
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19. Ultra Short acting barbiturate (5-10 mins) (intravenous anesthetics)
1- Thiopental Sodium :
▪ Replacement of C-2 O by S → ↑ lipid solubility.
▪ Rapid action (10 -15 sec) and rapid recovery .
▪ Used mainly as inducing anesthetic
▪ It has no analgesic properties
▪ Anesthetic state maintained by inhalation anesthetic eg
N20(nitrous oxide)
▪ it is a poor muscle relaxant.
2- Thiamylal Sodium:
▪ Following IV administration, the onset of action of these drugs is
rapid (within 30 to 40 seconds) and of short duration.
Thiopental (Pentothal) and thiamylal (Surital) are called
thiobarbiturates because they possess a sulfa molecule and are quite
similar pharmacologically
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20. 3- Methohexital sodium :
▪ It is a drug which is a barbiturate derivative. It is classified as short-acting, and
has a rapid onset of action.
▪ It is similar in its effects to sodium thiopental, a drug with which it competed in
the market for anaesthetics.
▪ Methohexital is primarily used to induce anesthesia.
Onset of action:
▪ Intramuscular—In pediatric patients, within 2 to 10 minutes
▪ Intravenous—Within 60 seconds
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21. Metabolism of barbiturates
Aromatic Hydroxylation , Glucuronide and sulfate conjugates at
position 5
▪ Phenobarbital
▪ Mephobarbital
Mephobarbital
Phenobarbital
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22. Oxidation of a substituent at C-5 forms alcohols
▪ Secobarbital
▪ Amobarbital
▪ Oxidation of a substituent at C-5 forms alcohols, and these undergo further oxidation to
form ketones or carboxylic acids. The barbiturates containing a propene at the fifth
position inactivates CYP450 by alkylation of the porphyrin ring of CYP450
Secobarbital
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23. Oxidative desulphation of 2-thio barbiturates
▪ Thiopental is extensively metabolized, primarily in the liver, resulting in only 0.3% of an
administered dose being excreted unchanged in the urine. Ring desulfuration leads to the
generation of an active metabolite, pentobarbital, that exists in concentrations
approximately 3-10% that of the parent concentration.
Thiopental Pentobarbital
desulfuration
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24. Now barbiturates get minimal use as sedatives & hypnotics (Why)?
1. They have higher toxicity, that cause greater CNS depression.
2. They induce many of the liver metabolizing enzymes.
3. Barbiturates cause tolerance and, often physical dependence.
4. They are not antagonized by flumazenil
✓ When an individual addicted to barbiturates, sudden withdrawal should be avoided, because
it can cause grand mal seizures, which lead to a spasm of the respiratory musculature,
producing impaired respiration, cyanosis, and possibly death.
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25. ▪ Melatonin (N-acetyl-5-methoxytryptamine) is the hormone responsible for regulation of
circadian and seasonal rhythms.
▪ Their endogenous ligand, melatonin ,at times referred to as “the hormone of darkness,” is
N-acetylated and O-methylated product of serotonin found in the pineal gland and is
biosynthesized and released at night and may play a role in the circadian rhythm of
humans.
▪ Melatonin synthesis is controlled by light–darkness cycles, increased during the night and
suppressed during the day , reaching a concentration peak at night (between 02:00 to
04:00).
▪ In the brain, three melatonin receptors (MT1, MT2, and MT3) have been characterized.
▪ Activation of the MT1 receptor results in sleepiness, whereas the MT2 receptor may be
related to the circadian rhythm. MT3 receptors may be related to intraocular pressure.
Melatonin Receptor Agonist
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26. ▪ The melatonin molecule was modified mainly by replacing the nitrogen of the indole ring with a carbon to give an
indole ring and by incorporating 5-methoxyl group in the indole ring into a more rigid furan ring.
Ramelteon :
▪ It was the first melatonergic agonist to be approved by the US FDA for the treatment of insomnia in 2005.
▪ In vitro binding studies showed that its affinity for MT1 and MT2 receptors is 3–16 times higher than that of
melatonin. The affinity of ramelteon for the MT1 receptor is eight times higher than that for the MT2 receptor. This
selectivity suggests that ramelteon targets sleep onset more specifically than melatonin
▪ It is used for the treatment of insomnia.
Tasimelteon
▪ It is a melatonin receptor agonist ,It exhibits a high affinity for MT1 and MT2 melatonergic receptors in humans
▪ It is the only drug approved by the US FDA and the EMA for treating non-24-hours sleep-wake rhythm disorder
(in sighted and blind people) .
Ramelteon
Tasimelteon
Melatonin
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27. Orexin Receptor Antagonists:
Belsomra(Suvorexant):
▪ Suvorexant, an orexin receptor antagonist (ORA), is the first in a
new class of drugs in development for the treatment of insomnia .
▪ It may help you fall asleep and stay asleep longer, so you can get
a better night's rest.
▪ Suvorexant belongs to a class of drugs known as sedative-
hypnotics, approved August 2014.
Orexin Receptor agonist Function:
▪ Orexin also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite.
▪ The least common form of narcolepsy, type 1, in which the sufferer experiences brief losses of muscle tone
(cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.
Orexin receptor antagonist (ORA), is a new class of drugs in development for the treatment of insomnia.
▪ The drugs promote the natural transition from wakefulness to sleep by inhibiting the wakefulness-promoting
orexin neurons of the arousal system.
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28. Lemborexant (Dayvigo):
▪ The FDA has approved lemborexant (Dayvigo – Eisai), an orexin receptor
antagonist, for treatment of sleep-onset and/or sleep-maintenance
insomnia in adults.
▪ It is the second orexin receptor antagonist to be approved for this
indication; suvorexant (Belsomra) was the first.
▪ DAYVIGO is contraindicated in patients with narcolepsy.
▪ U.S. FDA Approves lemborexant for the Treatment of Insomnia in Adult
Patients - Dec 23, 2019.
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29. Exercise:
2. Which the barbiturates shown below has a short duration of action?
1. All of the following structures are an active barbiturate, Except:
a b c d
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30. 3. Design a novel barbiturates with a high potent, rapid onset and long-acting of action,
based on the structure-activity relationship and pharmacological properties, and rationalize
your opinions.
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31. Summary Classification of
Sedative-Hypnotic
Drugs
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32. THANK YOU
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