1. بسم الله الرحمن الرحيم

2. By Prof. Dr/ Nadia Mahfouz Pharm. Chem. Department
CNS Drugs (6 hr)
Steroidal Hormones (3 hr) By
Prof. Dr/ Nadia Mahfouz
Pharm. Chem. Department
October 6 University
8/7/2019

3. Lecture…Lecture…Lecture
8/7/2019
References
Lecture…Lecture…Lecture
Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, J.N.Delgado and W.A.Remers eds., 13th edition, Lippincott-Raven, Philadelphia, (2012).
T. L. Lemke, D.A. Williams, V. F. Roche and S. W. Zito: Foye’s Principles of Medicinal Chemistry 8th edition, Lippincott Williams & Wilkins, Philadelphia, (2013).
Burger’s Medicinal Chemistry, M. E. Wolf ed 7th edition, John Wiley
and Sons NY (2010).
4. Allen, Loyd V., Jr Remington: The Science and Practice of Pharmacy. 22nd Ed, (2012).
5. Pharmaceutical chemistry notes 2017/2018
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4. Objectives principles that highlight modern medicinal chemistry
1) It is planned to provide students with the fundamental
principles that highlight modern medicinal chemistry
aspects of the following classes of central nervous
system (CNS) drugs which including CNS depressants and
stimulants.
2) The students study in this lecture general anesthetics
and sedative hypnotics as a class of CNS depressants.
2) It is necessary to identify and learn the students chemical
structures, chemical nomenclatures, generic names of drugs
of each group.
3) The students should also study the mechanism of action,
identify the pharmacophoric moieties and their effects on
their pharmacological activity.
4) It is necessary also to learn the students the method of
synthesis and analysis of each drug.
5) The students study also the biotransformation of each
drug in the class member.
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5. CNS Drugs Central Nervous System: Brain Spinal cord
CNS Depressants (4hr)
CNS Stimulants (2hr)
Central Nervous System:
Brain
Spinal cord
Brain is the most complex organ.
It works into two opposing forces,
excitation (stimulation) and inhibition
(depressing)
ANATOMY SUMMARY: The Central Nervous System
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6. CNS Depressants
Depression of neuronal activity in CNS leading to slow down or depress the CNS function.
General Anesthetics.
Sedatives & Hypnotics.
Psychotherapeutic Drugs.
Anxiolytics & Antipsychotics
Anticonvulsants.
Analgesics.
Central Muscle Relaxants
Brain
Spinal cord
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7. I) General Anesthetics 1) Inhalation Anesthesia
What are General Anesthetics?
CNS depressants that produce controlled and reversible loss of consciousness and sensation.
These Drugs block the transmission of pain.
Classification
1) Inhalation anesthetics (Volatile General Anesthetics)
2) Parenteral (Injectable) anesthetics (basal)
1) Inhalation Anesthesia
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8. Halogen What are drugs used as inhaled anesthetics?
Nitrous Oxide (N2O): (dentist , 1844)
(Ph Eur monograph 0416): N2O 44.01
Action and use: General anaesthetic; analgesic.
Low potency , cause hypoxia and used in combination with
more potent anesthetics for surgical anesthesia, popular
anesthetic in dentistry and undergoes no metabolism. It
causes euphoria.
Gases
Low boiling points
Liquids
Diethyl ether, Chloroform
How?
Halogen
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9. Fluronated Ethers (Fluranes)
Halogenated Inhaled General Anesthetics
Advantages: Potent and non flammables
A) Halogenated Hydrocarbons:
Halothane:
It causes hepatic toxicity because about 20% of dose is metabolized to toxic metabolite.
(Trifluoroacetic acid)
B) Halogenated Ethers:
Fluronated Ethers (Fluranes)
Enflurane (RT depression, cardiac arrhythmias, convulsion)
2) Isoflurane ) Desflurane
4) Methoxyflurane (causes nephrotoxicity)
5) Sevoflurane
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10. Sevoflurane Chemical Nomenclature???
1-(Trifluoromethyl)-2,2,2-Trifluoroethyl fluoromethyl ether
Higher potency and non-irritating to respiratory tract
Similar to desflurane in its pharmacologiocal actions
Low blood solubility, blood/gas PC is 0.6
(Induction and recovery are rapid)
Incidence of nephrotoxicity or hepatic toxicity is low.
3% of the administered dose can be metabolized.
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11. Fluoride impurities in liquid anesthetics
Aqueous extract made alkaline with NaOH and titrated with thorium nitrate using alizarine sulfonate as indicator till pink color is formed.
Th(NO3) F-
ThF4 (nonionisable)
Excess Th(NO3)4
Alizarine sulfonate
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12. What is the mechanism of action?
1. Meyer-Overton theory:
Lipid soluble drug interacts with the cell membrane results in disrupted of the phospholipid bilayer and directly prevent normal ionic conductance and produced anesthesia.
2. Ion Channel and Protein receptor hypothesis:
General Anesthetics interact with receptors in CNS that
allosterically modulate the activity of ion channels (e.g. chloride,
sodium, potassium , calcium channels). GABAA receptor:
Inhaled Anesth. enhance chloride ion Conductance into cell
Lead to hyperpolarize the cell membrane and prevent pulse.
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13. 2) Injectable (Basal) Anesthetics
Agents that achieve certain degree of unconsciousness
before inhalation anesthesia, they include:
Ultrashort acting barbiturates e.g thiopental, thymilal
Cyclohexanone derivatives e.g ketamine
Phenol derivatives e.g propofol
Imidazole derivatives e.g etomidate
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14. 1) Ketamine Hydrochloride (BP 2004)
.HCl
Norketamine
Active metabolite
Chem. Nomenclature:
(±)- 2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
S(+) is 2-3 times more potent than R(-)
Very potent, rapidly acting anesthetic agent, it used IV or IM
Short duration of anesthetic activity (1.0 – 2.5 min).
One of its metabolites is Nor-ketamine (major) , which retains
significant activity at the NMDA receptor and may account for
some of the longer lasting effects of ketamine (1/3 potency of
ketamine).
Ketamine acts as noncompetitive antagonist at NMDA receptor.
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15. Etomidate 2) Imidazole derivative
Imidazole carboxylic acid derivative.
Marketed as more potent R(+) isomer.
Water insoluble, oil soluble, rapidly penetrates into brain.
Rapidly metabolized in plasma and liver via esterases.
Exert anesthesia via positive modulation of GABAA
receptor.

16. Q1: Mention the generic name and chemical nomenclature of
each following drugs
(1) (2) (3) (4)
Q2: Draw the structure of the toxic metabolite of drug #1
Q3: Mention by equation a method for determination of fluoride impurity of
any drug (#1 or 2).
Q5: Mention the chemical group of drugs # 1 - 4
Q6: Fluranes including drug # ……………………………….
Q7: Mention the generic name, chemical nomenclature
and route of administration of the given drug 1-4)
Q8: Draw the structure of an active metabolite of drug # 3
Q9: Mention the mechanism of action of drugs 1, 3 &4
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17. II) Sedatives Hypnotics
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18. Ideal Sedative hypnotic causes normal sleeping.
Sedatives Hypnotics:
Produce nonselective reversible depression of CNS.
Cause drowsiness and facilitate the initiation and
maintenance of sleep, they are dose related.
Lower dose Sedative
Higher dose Hypnotic
Sedatives: mild CNS depressant, cause quieting effect and
relaxation but not induce sleep.
Hypnotics: Strong CNS depressant, produce sleep.
Ideal Sedative hypnotic causes normal sleeping.
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19. Characters Certain common physicochemical and structural features.
All compounds contain polar and non-polar moieties.
The polar moiety (high hydrophilic characters).
Their structures generally resist metabolism.
The whole molecule has partition coefficient around 100 (Log P = 2).
Activity 2
Log P
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20. Classifications of
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21. 1)Barbiturates
Structure
Acyclic Ureides
Cyclic ureides
(Barbiturates)

22. I) Barbiturates 5,5-Disubstituted Barbituric acid
Barbituric acid (Pka ~ 4) is water soluble,
very polar, , hence inactive. Why???
Barbituric acid
monolactim
dilactim
trilactim
It should be substituted at position 5 to increase
lipid solubility.
5,5-Disubst. or 1,5,5-trisubst. are only active
The duration of action ranging from ultrashort to
long depends on type of substituents.
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23. USP -al European -one Generic name R1 R2 R X Phenobarbital H O
Long acting (> 6h)
Phenobarbital
C2H5
C6H5 H O
Intermediate (3-6h)
Amobarbital
Short (< 3h)
Secobarbital
Ultrashort
Thiopental
Methohexital
CH3 S

24. Phenobarbital: Thiopental Sodium SAR 5-Ethyl-5-phenylbarbituric acid
Uses: Sedative hypnotic & anticonvulsant
Thiopental Sodium
5-Ethyl-5-(1-methylbutyl)-2-thiobarbituric
acid sodium salt
Uses: General anaethatic
SAR
X = O active
X = S faster onset & ultrashort
Acting e.g thiopental (surgical
anesthetics) why? Higher partition
coeffecient.
R1 + R2 = C atoms.
Branching & unsaturation produce higher activity and short duration.
Aromatic or alicyclic increases potency
& long duration.
5-Phenyl gives higher lipophilicity
( anticonvulsant activity)
Polar substituents abolish activity!!
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25. Mechanism of Action
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26. Miscellaneous Alcohols NonBarbiturate sedative hypnotics
Chloral hydrate CCl3CHO.H2O
Relatively save sedative hypnotic, inducing sleeping
within half an hour and lasting for 6 hours.
It used mainly in children and elder, and patients when failed
to other drugs.
It is metabolized into trichloroethanol (active), trichloroethanol
glucuronide and trichloroacetic acid (inactive).
It exerts its action through enhancing the binding of GABA to
its receptor as barbiturates and benzodiazepines.
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27. Disadvantages of Chloral Hydrate : bad taste and odour
Its adducts with betaine (1:1)
CCl3CH(OH)2 : (CH3)3N+-CH2COO-
or with pentaerythrytol (4:1) do not have these disadvantages.
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28. Recent Sleep inducing agents
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29. Classification 1) Z-drugs Zolpidem Z-Drugs
Melatonin-1 receptor (MT1 ) agonists
1) Z-drugs
Highly selective for α1 subunit of BzR binding site on GABAA
they include:
1) Zolpidem, Imidazopyridine derivative
2) Zaleplon, Pyrazolopyrimidine derivative
3) Zopiclone and esZopiclone, Pyrrolone
derivatives
Zolpidem
Imidazopyridine derivative
Rapid onset of action and good oral bioavailability
(lipophilic and has no ionizable group at physiological pH
Short acting hypnotic, (metabolizes to inactive compounds).
Most common drug prescribed for insomnia.
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30. 2) Melatonin-1 receptor (MT1 ) agonists
Activation of MT1 receptor results in sleeping
Its endogenous ligand, melatonin (N-acetyl-5-methoxytryptamine)
hormone of darkness, is N-acetylated and O-methylated product
of serotonin and is biosynthesized and release at night.
Melatonin is a poor hypnotic drug because of its poor potency,
poor adsorption, poor oral bioavailability, rapid metabolism and
nonselective effects.
Melatonin was modified by replacing the NH of the indole ring by
CH2 to give indane ring and by incorporating 5-OCH3 group in the
indole into a more rigid furan ring, this modification results in
Ramelteon
Ramelteon
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31. Ramelteon It is more effective in initiating sleep than melatonin.
It is a MT1 selective agonist (8 times more than MT2 ).
It is more effective in initiating sleep than melatonin.
It is more efficacious than melatonin but less than
benzodiazepines as hypnotic.
It has no addiction liability.
It has recently approved for treatment of insomnia.
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32. for the compounds which are inactive and the class of the active one
Q1: Which of the following compounds are active as sedative hypnotic, giving reasons
for the compounds which are inactive and the class of the active one
(long, intermediate, short, ultrashort acting)
Q2: Mention the chemical nomenclature of compound # 3 in Q1
Q3 Mention the mechanism of action of barbiturate
Q4: Mention the chemical class of drug #5
Q5: Draw the structures of metabolic products of drug # 5,
are these metabolites active or inactive?
Q6: How you can overcome the bad taste and odour of drug # 5?
(5)
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33. Q7: Mention the generic name, use and chemical group
of the given drug.
Q8: Is this drug short or long acting, justify your answer.
Q9: mention the generic name of the given compound
Q10: Can this compound used as hypnotic? Why?
Q11: Carry out modifications of the given lead compound
to obtain a hypnotic drug.
Q12: What is the advantages of the obtained drug than the
lead compound
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