CHAPTER THREE

DRUGS ACTING ON THE CENTRAL NERVOUS SYSTEM

BY: TESFAYE.N (B.Sc,B.Pharm,M.Sc)

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HARAMBEE UNIVERSITY,2022
 OUTLINE

3.1 Introduction
3.2 Sedatives & hypnotics (barbiturates, ureides, amides &
imides, alcohols, carbamates, aldehydes & ketones)
3.3 Anticonvulsant drugs
3.4 Major tranquilizers(neuroleptics)
3.5 Minor tranquilizers(anxiolytics)
3.6 Central skeletal muscle relaxants
3.7 CNS stimulant drugs (Analeptics, Antidepressant
drugs, CNS adrenergics, Miscellaneous stimulants)
3.8 Anti-parkinsonian drugs
3.9 Narcotic analgesics & antagonists
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 3.1 Introduction
• The CNS is an extremely Complex and heterogeneous
system.

• It is the major coordinating system of the body & source

of adjustment of an organism to its environment.

• Function-rapid communication system and is responsible

for moment to moment control of various body activities.

• It regulates-rapidly changing visceral events, muscle

contractions, secretions of some endocrine glands and
functioning of the body system.

• The CNS is more sensitive to effects of drugs than any

other system of the body.
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 Drugs that affect the CNS can:
•Selectively relieve pain
•Reduce fever
•Suppress disordered movement
•Induce sleep or arousal
•Reduce appetite
•Allay the tendency to vomit
•Be used to treat anxiety, depression, schizophrenia,
Parkinson’s Disease, Alzheimer’s Disease, epilepsy,
migraine, etc.

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 Class of CNS drugs
1. CNS depressants (most important)
– sedative/hypnotics
– anxiolytics
– general anaesthetics
– antiseizure drugs
– anti psychotics
–Analgesics
–Antiparkinsonians
2. CNS stimulants (mostly abused)
–General stimulants (Analeptics)
– Methyl Xanthine
– Central sympathomimetic agents
– Antidepressants
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 Biochemical basis of drug action on the CNS

How do they work?

 These interfere with the activity of the neurons in the CNS.
Activity is effected through neurotransmitters

Neurotransmiters-NT’s
NT’s are chemicals that are used to relay, amplify and modulate
electrical signals between a neuron and another cell.

N.B: An action potential cannot cross the synaptic cleft

 Implicated in:
 the normal biochemical functions of the CNS.
 Pathophysiology of various CNS disorders.

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 Common class of neurotransmitters
• Monoamines [NE, E, DA, 5-HT, Hist]
• Amino acids [GABA, GLY, ASP, GLU…]
• Quaternary ammonium cpd [Ach]
• Neuromodulators [CO and ammonia, purines [e.g.,
adenosine], eicosanoids]
• Neuropeptides: [dynorphin, enkephalins…]
• Neuromediators [cyclic AMP, cyclic GMP, and inositol
phosphates]
 In the brain, all these chemical compounds are synthesized
from
– D-glucose or from the essential amino acids
– The only exceptions are the vitamins, insulin, and
minerals, which are transported into the brain via a
specific transporter.
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 Common CNS neurotransmitters cont’d
i. Monoamines
• NE, DA and 5-HT
NE (ɑ and β)

• Widely distributed in the CNS.

• Involved in the regulation of mood, alertness, BP as well as
inhibition of feeding centre.
• Effect of ↑ed activity → alertness, insomnia, Psychosis & anorexia.
• Effect of ↓ ed activity → lethargy, sluggish mental behaviour, &
Depression

5-HT (5-HT1, 5-HT2, 5-HT3, 5-HT4 & 5-HT5)

• Widely distributed in the CNS.
• Regulates mood, appetite (↓feeding centre →anorexia),
↓mediation of pain sensation, control temperature (5-HT↑ during
cold and ↓ during warm).
• Effect of ↑ed activity → ↑mood, temperature, Psychosis & anorexia
• Effect of ↓ ed activity → lethargy, Depression & Phagia.

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 Common neurotransmitters cont’d
DA (D1 & D2)
Sites and functions
• 75% in the substantia nigra, and
corpus striatum (basal ganglia)
• Control of the movement of sk.ms.
• 15% mesolimbic
• Control normal behaviour
• 10% _ In hypothalamus-hypophyseal tract: ↓ prolactin and GH
– In CTZ: Mediates vomitting.
– In the hypothalamus: ↑ temperature
Effect of ↑ed activity → Chorea, Psychosis, abnormal behaviour
(schizophrenia) & vomitting
Effect of ↓ ed activity → Parkinsonism, ↑prolactin, & antiemesis.

• ↓of monoamines → CNS depression

• ↑of monoamines → Psychosis & Schizophrenia

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 Common neurotransmitters cont’d
Ach (M1 & M2)
• Widely distributed in the CNS
• Regulation arousal, learning, and memory.
• Controls sk.Ms movement (voluntary)

Effect of ↑ activity → parkinsonism

Effect of ↓ activity → Chorea, senile dementia (Alzheimer’s
disease)
o So it must balance between DA and Ach in the CNS.

 Imbalance → parkinsonism or Chorea

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 Common neurotransmitters cont’d
ii.Amino acids

 Two types
Inhibitory a.as
GABA
Glycine
Excitatory a.as
Glutamate (Glu)
Aspartate (Asp)

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 Common neurotransmitters cont’d

• Histamine: (H1)
arousal, wakefulness
• Purines
• Adenosine
• Neuropeptides:
• Opioid peptides (dynorphins, enkephalin)
• Cholecystokinins, etc.
• Miscellaneous
• NO
• CO

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 Blood-Brain Barrier: A Physicochemical Principle to Drug Entry into CNS

 Not all substances in the bloodstream can readily gain

entry into the brain.
 The term blood brain barrier [BBB] is usually applied to
the lack of passage of certain drugs or other
exogenously administered chemicals into the brain.
 It behaves primarily as a stringent gatekeeper between
blood and brain to maintain homeostasis.

 The most likely location of the blood-brain barrier

– The capillaries of the brain

Note: The concentration in the brain of these bioactive

substances appears to be carefully regulated.
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 Cont…

 A large number of lipid-insoluble endogenous substances are

known to be transported into the brain.
– These include glucose, amino acids, simple carboxylic
acids, and purines.

 Brain capillaries contain many more mitochondria than do

other capillaries.
 Sufficient lipid solubility to allow the drug molecule to cross
BBB via passive diffusion

Quesition
Are there any functional group(s) presented in the molecule
that are easily degraded in the periphery (blood and/or liver) to
give an ionizable and/or water soluble metabolite(s)?
If so, it will probably not have any appreciable CNS activity.
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 3.2 Sedatives & hypnotics (barbiturates, ureides, amides
& imides, alcohols, carbamates, aldehydes & ketones)

 Tranquilization is a mild form of CNS depression producing a

state of behavioral change in which the animal is relaxed and
unconcerned with his surroundings
 Agents producing a state of tranquillization are called
tranquillizers or ataractics.

 Sedation refers to a degree of CNS depression in which the

patient is awake but calm and free from
nervousness.
 Sedatives are drugs which calm or exert a quitting effect (not
necessarily induce sleep)

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 Cont…
 Hypnosis is depression of CNS equal to normal sleep.

 Hypnotics are drugs which induce sleep when natural sleep is

impossible.
Note: The degree of CNS depression Sedation is higher than
tranquillization but lower than hypnosis.

 Sedative - hypnotics: are the drugs which depress the CNS

sufficiently to cause lethargy, drowsiness and indifference to
the surroundings.
 They decrease locomotor activity.

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 What is sleep?
 sleep is difficult to define…
o little movement
o a stereotypic posture
o reduced response to stimulation
o reversibility
 Importance of sleep
• One-third of our life is spent in sleep,
• both wakefulness and sleep are considered to be active
processes
 has a major influence on:
• an individual's physical, social, and psychological well-
being.
• Disturbances during sleep may impair daytime function

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 Sleep Factors

• ACh: cholinergic agonists can initiate REM sleep from NREM

post microinjection
(arecoline, bethanechol, AChEI’s)
• cholinergic antagonists hinder the transition to REM sleep
(atropine, scopolamine)
• Catecholamines: an intact system is necessary for REM sleep
(dopamine, NE agonists/antagonists)
• Serotonin
• GABA (the most important)

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 Neurohumoral modulators

sleep and circadian rhythms affect hormonal release:

• growth hormone
• prolactin
• melatonin

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 Cont...
 Growth Hormone
– GH shows stable plasma levels with secretary pulses at the onset of
NREM sleep
– amount of GH released correlates with NREM sleep time
– older people show less GH secretion and less NREM sleep
 Melatonin
• “hormone of darkness”
• Secretion is decreased by bright light, physical activity
• May effect circadian rhythms, sleep processes
• Orally, leads to faster sleep onset, longer sleep time, but MOA is
unclear!

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 Cont...

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 sedative-hypnotics

Level of CNS depression:

calmness, drowsiness, sleep, anesthesia, …
barbiturates

BDZ

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 Cont...
Classification

“The hypnotic drugs are not characterized by common structural

features. Instead, a wide variety of chemical compounds have
been used in clinical therapy.”
• Barbiturates
• Benzodiazepines
• Halogenated alcohols (chloral hydrate, ethchlorvynol)
• Heterocyclic compounds (piperidinediones,thiazoles,
imidazopyridines, pyrrolopyrazinones,pyrazolopyrimidines)
• Antihistamines
• Other sedative-hypnotics (valnoctamide, propofol, plant extracts,
endogenous sleep factors, melatonin derivatives)

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 Cont...
General Biochemical Principles

• CNS active,
• hence must cross blood-brain barrier
• Lipophilicity is a major SAR feature
– Activity + Potency + Onset
• Duration of action depends on distribution and metabolism
• SAR only within a given drug class, not across classes

Indications
The sedative-hypnotics tend to illicit effects that include:
• anxiolytic effects (anti-anxiety)
• sleep-induction
• anticonvulsant / anti-seizure properties
• anesthesia
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 I. Barbiturates
• Are the 5,5 disubstituted derivatives of barbituric acid.

A saturated
5
triketopyrimidine. 4
1 3
2

• Have a wide range of dose dependent pharmacological actions

related to CNS depression.
• Usage as sedative, hypnotic, anticonvulsant, anesthetic.
• May enhance inhibitory synaptic transmission: potentiate
GABAA ion channel +……..

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 Cont...
Synthesis

Malonic Acid Urea Barbituric Acid

 Barbituric acid is synthesized by a condensation reaction that results

in the release of H2O (dehydration) and the heterocyclic pyrimidine

 Further substitution of side chains on the ring produce the

pharmacologically active barbiturates

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 Cont...

General Structure of barbiturates

Substituents at R1 and R2 positions result in different drugs

With different duration of action

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 Cont...
SAR of Barbiturates
• C-5 must be disubstituted (two side chains essential ).
– Barbituric acid is inactive.
– Two methyl derivatives are also inactive.
– Activity appears when two ethyl groups are present at C-5
• Potency goes up with increasing substituent size but..
– there is a maximum of 6 carbons per substituent
– maximum of 10 carbons for both substituents
– Alicyclic and aromatic substituents at C-5 impart greater
potency than the aliphatic with the same no. of C-atoms
• An unsaturated chains at C-5 show greater potency than the
saturated analogues with the same no of carbon atoms.

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 Cont...
• Within the same series, branching of the C-5 substituents
increases potency and shortens duration of action.
• Pentobarbital > amobarbital
• Branching is most effective at 1st carbon.
• Polar substituents decrease potency, halogens increase potency
• N-methylation (alkylation) shortens duration of action and
shortens onset. Only one of the nitrogens can be substituted.
• Replacement of carbonyl O with S at C-2 results in compounds
with very short onset and short duration.
– E.g. Thiopentone Vs Pentobarbital
– Maximal concentrations are reached quickly
– Not useful as sedative-hypnotics.
• Induction of anesthesia.
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 Cont...

• Two sulfur substitutions (for O) results in inactive compounds

with too much lipophilicity.

O O O
O
HN NH HN NH

O S
Pentobarbital Vs Thiopentone

• Thiopentone is the prototype ultra short acting barbiturate

• It is the 2-thio iso stere of pentobarbital.

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 Cont...
Generally,
• Within the general framework of the barbiturate structure, potency
can be predicted using lipophilicity and metabolic susceptibility
arguments.
 Increasing the no of carbon atoms
 Branching
 Unsaturation
 Introduction of alicyclic substituents
 “ “ aromatic “
 Introduction of halogens
 All increase lipophilicity of barbituric acid derivatives
 Lipophilicity enables to cross blood brain barrier.
 However, hydrophilicity is also important as it determines the
solubility of the drug in the biological fluid.
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 Cont...

Duration of action depends on distribution and metabolism

What will effect activity, distribution and metabolism?

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 Cont...

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 Cont...

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 Cont...
Classification of barbiturates

Drug R1 subst R2 subst Duration Chemical Name

Phenobarbital -CH2CH3 Long 5-ethyl-5-phenylbarbituric

(Luminal) acid

Amobarbital -CH2CH2CH(CH3)2 Intermediate 5-ethyl-5-isopentylbarbituric

-CH2CH3
(Amytal) acid

Butabarbital -CH2CH3 -CH2CH2CH3 Intermediate 5-ethyl-5-sec-butylbarbituric

(Butisol) CH3 acid

-CH2CH3 -CH2CH2CH2CH3 5-ethyl-5-(1'-methylbutyl)-

Pentobarbital Short
CH3 barbituric acid
(Nembutal)

Secobarbital -CH2CH CH2 -CH2CH2CH2CH3 Short 5-Allyl-5-(1'-methylbutyl)-

(Secontal) CH3 barbituric acid

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 Cont...

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 Cont...

Acidity of barbiturates
 The protons on the nitrogen are acidic.
 ∆ es in urinary PH greatly influences their excretion
 This is particularly true during overdoses
 urinary alkalinization enhances elimination of barbiturates

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 II. Non barbiturate sedative hypnotics

A. UREIDES

RCOCl + H2NCONH2 RCO-NH-CO-NH2

Urea Ureid
Dicarboxylic acids and their derivatives react with urea to form cyclic ureids

O O
COOH
+ NH2CONH2 HN NH
COOH
O
Oxalic acid Urea Cyclic ureid

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 Cont...

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 Metabolism of Alcohol
Cont...

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 Other Sedative-Hypnotics:
1. NBRAs (Nonbenzodiazepine -receptor agonists

Zaleplon,
zolpidem and
zoplicone (eszoplicone)

These are newer agents do not fit

into either the benzodiazepine or
barbiturate

 all of these drugs have chemical structures

that are unrelated to the benzodiazepines.
 all bind to the benzodiazepine receptor at the
GABA-A receptor and increase the effect of
GABA at the receptor.

Note: The NBRAs have shorter durations of action 46

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 Other Sedative-Hypnotics cont...
2. Melatonin agonists

Ramelteon is a new hypnotic agent that is in a chemical and

pharmacological class of its own.
• It is a chemical mimic of the endogenous hormone melatonin.
• is an agonist with affinity for two types of melatonin
receptors:
– (1) melatonin type 1 (MT1) and
– (2) melatonin type 2 (MT2).

 Ramelteon is a more potent agonist at the MT1 and MT2 receptors

than melatonin 47
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 3.3 Anticonvulsant Drugs

 Anticonvulsants, sometimes also called antiepileptics, belong

to a diverse group of pharmaceuticals used in prevention of the
occurrence of epileptic seizures.

 The goal of an anticonvulsant is to suppress the rapid and

excessive firing of neurons that start a seizure.

 Anticonvulsant drug decreases the frequency and/or severity of

seizures in people with epilepsy.
 Seizures are episodes of neurologic dysfunction arising from
abnormal synchronous activity of neurons.

 Epilepsy is a disease characterized by spontaneous recurrent

seizures. It is a group of disorders characterized by excessive
TESFAYE.excitability
N of neurons within the central nervous system.
 Cont…

TESFAYE. N
 Examples of anticonvulsant drugs
1. Phenytoin: one of the oldest and most widely used
anticonvulsants.
 It is used to control certain type of seizures, and to treat and
prevent seizures.
 It works by decreasing abnormal electrical activity in the brain.

2. Carbamazepine (Tegretol, Equetro): is an anticonvulsant and

mood-stabilizing drug used primarily in the
treatment of epilepsy and bipolar disorder.
 Structural features similar to phenytoin.

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 Cont…
3. Barbiturates: are sedative hypnotics with anticonvulsant
activities but only a few of them are used as
antiepileptic drug.
Mechanism probably related to increased GABA-mediated
chloride conductance

4. Primidone: is an anticonvulsant of the pyrimidinedione class,

but is metabolized rapidly by the liver to
phenobarbital (major) and phenylethylmalonamide
(PEMA) (minor), which are also anticonvulsants.

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 Cont…
5. Ethosuximide: is a succinimide anticonvulsan.

6. Valproic acid (Valproate): is a carboxylic acid compound,

structurally distinct from other current classes of anticonvulsants.

 Valproate is a liquid at room temperature, but it can be reacted

with a base such as sodium hydroxide to form the salt
sodium valproate, which is a solid.

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 Cont…
7. Benzodiazepines: can be used as anticonvulsants to decrease
seizures.
Two agents are frequently used, diazepam and lorazepam.

These are particularly suitable because of rapid action after

intravenous injection.

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 3.4 Major Tranquilizers(Neuroleptics)
 Antipsychotic (neuroleptic) agents are primarily used in the
therapy of schizophrenia, organic psychoses, the manic phase of
manic-depressive illness and other acute or chronic idiopathic
psychotic illnesses.
 psychotic illnesses is due to neurochemical defects of
dopaminergic and serotonergic pathways in the brain.

Antipsychotic Drug Classes

1. Typical Antipsychotics
• A class of antipsychotic drugs first developed in the 1950s
• Commonly used but not the best and not very selective
Examples: Phenothiazine compounds
Thioxanthene compounds
Butyrophenone compounds
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 Cont…
2. Atypical Antipsychotics
• Also known as second generation antipsychotics
• Less side effects (Parkinson like), more selective
Examples: Clozapine, Risperidone, Olanzapine, Ziprazidone
Quetiapine and Amisulpride

The mechanism of action of antipsychotic drugs are only

partially known
Mechanism of action: most antipsychotic agents act as
antagonists at pre- and postsynaptic dopamine receptors, that
is, by blocking dopamine from binding to its receptor sites.

NOTE: The three most accepted atypical drugs are; clozapine,

risperidone and olanzapine

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 1. Phenothiazine Derivatives
First synthesized in 1950, chlorpromazine was the first drug
developed with specific antipsychotic action, and would serve as
the prototype for the phenothiazine class of drugs.

Phenothiazine derivatives are chemically characterized by a

lipophilic fused tricyclic system (the phenothiazine nucleus)
linked through the nitrogen atom of the central ring to a
hydrophilic aminoalkyl substitutent (the tertiary basic side
chain).

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 Cont…
Structure-Activity Relationships
The pendent amine functionality (Site A )

Intervening alkyl chain between the

central ring and the terminal amino group
(Site B )

A tricyclic ring system with six- or seven-

membered central ring (Site C )
Y=N, X=S

It is postulated that phenothiazines interact with dopamine

receptors at three distinct sites A, B, C.

The order of importance in terms of structure activity is B > C > A.

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 Cont…
SITE B
 A three carbon atom chain is needed for optimum
neuroleptic activity
 This alkyl group should be bonded to a nitrogen atom

 A substituent at 2-position of this 3 carbon atom chain affects

activity. When R1 is a H atom the activity is optimal.

 Whereas small alkyl substituents such as methyl are tolerated

at the C2 carbon, larger substituents (for example R1 : phenyl,
dimethylamino) that restrict the free rotation decrease
neuroleptic potency

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 Cont…
SITE C
 The phenothiazine ring is not planar.
 For example, the angle between the two phenyl planes
is 159o in chlorpromazine and 141o in perphenazine.

 Phenothiazine ring is not necessary for neuroleptic

activity. Other planar tricyclic systems like thioxanthenes
are active.

 Substituents at 2-position (X) of the phenyl ring improve

activity.
 Electron withdrawing substituents such as halogens,
methoxy, acetyl, trifluoromethyl increase activity.

 Substituents at 1, 3, 4-positions decrease activity 59

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 Cont…
SITE A
Nature of the amino group
 The size and nature of the basic amino group has
considerable influence on the behavior of the phenothiazine
neuroleptics, because the molecule has to fit into a narrow space.

 A tertiary amine has optimal activity; presence of alkyl groups

larger than methyl or replacing methyl groups with hydrogen
atoms decrease activity.

 On the other hand, if the nitrogen is part of a heterocyclic ring

(such as in N-methylpiperazine and piperidine compounds),
neuroleptic potency may not be reduced.

 The effective size of the piperazine ring for instance, is smaller than
that of the diethylamino group. 60
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 2. Butyrophenones
 Haloperidol, the most widely used classical antipsychotic drug
in this class.
 Droperidol, often used for neuroleptanalgesic anesthesia and
sedation in intensive-care treatment.
 Benperidol, the most potent commonly used antipsychotic
(200 times more potent than chlorpromazine).

Structure Activity Relationships of Butyrophenones

All butyrophenone derivatives displaying high antipsychotic
activity have the following general structure

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 Cont…

 p-fluorobutyrophenone skeleton is essential for neuroleptic

activity.
 All potent compounds have a fluorine substituent in the para
position of the benzene ring.
 Replacing F with other groups like Cl-, Br-, -OCH3 decreases activity.
 Replacement of the keto group by a thioketone group decreases
neuroleptic activity.

 Reduction of the keto group to alcohol decreases potency.

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 Cont…
 Lengthening, shortening, or branching of the three carbon
(propyl) chain decreases neuroleptic potency.

 Variations are possible in the tertiary amino group without loss

of neuroleptic potency.

 Nitrogen atom is usually incorporated into a six membered ring

(piperidine, tetrahydropyridine, or piperazine), which usually has
another substituent in position 4.

 R2 group should be aromatic.

 R3 group helps with activity, could be a – OH group as in the case

of haloperidol
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 3. Thioxanthene Derivatives

 Structurally related to phenothiazine derivatives, they resulted from

isosteric replacement in chlorpromazine and analogs.

 Their pharmacological actions and adverse effects are very similar to those
of phenothiazine derivatives.
 Examples : chlorprothixene, flupentixol and thiothixene

Note: The structure-activity relationship of the thioxanthene

mimic that of the phenothiazines.

 The thioxanthene ring is also nonplanar: the angle between the two phenyl
planes is 142o in chlorprothixene, 150o in flupentixol and 142o in thiothixene.
21/10/2023
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 3.5 Minor Tranquilizers(Anxiolytics)
• Anxiolytic agent:
– reduce anxiety
– exert a calming effect with little or no effect on motor or
mental functions.
• Minor tranquilizers:
– The degree of CNS depression that is minimum consistent
with therapeutic efficiency.
• Two categories of drugs are extensively used as anxiolytic
drugs
– benzodiazepines (e.g., Lorazepam, alprazolam)
– Nonbenzodiazepines (e.g., buspirone)

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 Benzodiazepines: Prototype cpd
Benzodiazepines: some profile
 relatively safe compared to barbiturates,
 wide margin of safety between anti-anxiety doses and
sedation, respiratory depression doses
 low enzymatic induction
MDCH334

 cross reaction with other drugs is lower

barbiturates
 short onset times
BDZ
 duration varies with compound

Clinical use:
Used as anxiolytics, sleep inducers, anesthetics,
anticonvulsants,
TESFAYE. N muscle relaxants,… 66
 Antianxiety agents: General Principles

• CNS active
• Hence must cross blood-brain barrier
• Lipophilicity is a major SAR feature
Activity + Potency
• Duration of action depends on distribution and metabolism

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 Structural classes & physicochemical property

The benzodiazepines are:

lipophilic
weak bases
and are absorbed better in the duodenum. 68
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 Structures of some commercially available benzodiazepines

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 SAR

The following major chemical features are important for biological activity.

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 hydroxylation

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 Miscellaneous Anxiolytics

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 3.6 Central skeletal muscle relaxants

What are Skeletal Muscle Relaxants?

They are drugs used to induce skeletal muscles relaxation.

 The centrally acting muscle relaxants tend to depress the central

nervous system by keeping the muscle tonus under control.

 The exact mechanism of action of skeletal muscle relaxants is not

well known at this time.

 The use of these drugs may result in a mild general sedative effect
producing an overall relaxation.

 Have an onset of action between 30 and 60 minutes

 Duration of action varies among the drugs

Classification: see next slide
TESFAYE. N
 Skeletal muscle relaxants

Peripherally acting Spasmolytic

Neuromuscular Centrally Direct

blockers or motor acting acting
end plate blockers
Depolari Baclofen
zing (act on Dantrole
blockers spinal
Diazep ne
Atracu cord)
am
Succin
rium ylcholi act(
Mivac
Panc
D- ne on
urium
uron
tub spinl
ium )cord
oc
Vecu
ura
roni
rin
um
eor
Cur
are
Pr(
oto
TESFAYE. N typ
 Baclofen

 It acts through GABA- B receptors

 It causes hyper polarization by increased K+ conductance,

reducing calcium influx and reduces excitatory transmitter in
brain as well as spinal cord

 It also reduces pain by inhibitory substance P. in spinal cord

 It is less sedative
 It is rapidly and completely absorbed orally
 It has a half life of 3- 4 hours
 It may increases seizures in epileptics
Baclofen

 It is also useful to prevent migraine.

TESFAYE. N
 Benzodiazepines

 Sedative and hypnotic drugs

 Tranquilizing effect
Diazepam
 Diazepam: Diapam, Diazem, Lizan, Nervium

 aside from relieving muscle pains and spasms, it also alleviates

convulsion, and anxiety related symptoms.

 It acts on the brain and nerves and produced a temporary

calming effect on the user
 Side effects: Sedation and numbness

TESFAYE. N
 Dantrolene
 It acts directly
 It reduces skeletal muscle strength by interfering with
excitation-contraction coupling into the muscle fiber, by
inhibiting the release of activator calcium from the
sarcoplasmic stores.

 It is very useful in the treatment of malignant hyperthermia

caused by depolarizing relaxants.

 This drug can be administered orally as well as intravenously.

Oral absorption is only one third.

 Half life of the drug is 8-9 hours.

TESFAYE. N
 3.7 CNS Stimulant Drugs
 Central nervous system stimulants are drugs that stimulate
the CNS and/or improve specific brain functions.

 They are drugs which increase the muscular (motor) and the
mental (sensory) activities.
 These drugs are relatively non-specific in action and affect all
parts of the CNS when given in sufficient dosage.

 These drugs are used to counteract the excess depression of

CNS caused by over dosage of anaesthetics and toxicity of CNS
depressant drugs or some poisonings.
 Death under these conditions results from central respiratory
or vasomotor failure or both.

TESFAYE. N
 Cont…
General signs and symptoms of CNS stimulation:
• ↑ Heart rate.
• ↑ Respiratory rate.
• Instability & restlessness.
• Muscle twitching (tremors).
• Hair erection.
• Convulsion but at high dose may lead to death.

TESFAYE. N
 Cont…
Classification of CNS stimulants
1. Cerebral stimulants.
2. Psychomotor stimulants e.g. Amphetamine.
3. Medullary stimulants.
4. Psychotomimetic stimulants (hallucinogenic drugs). e.g.
cannabis, lysergic acid diethylamine (LSD), THC
(tetrahydrocannabinol).
5. Spinal cord stimulants

TESFAYE. N
 Analeptics
 Analeptics are drugs that act at the level of brain stem and
stimulate medullary respiratory centre.
 These agents have resuscitation value in respiratory depression,
coma or unconsciousness.
 The term analeptic is derived from Greek word ‘analeptikos’
that means restorative.
Examples of brain stem stimulants/analeptics
3.7 CNS stimulant drugs
Doxapram, (Analeptics, Antidepressant
Bemegride, drugs, CNS adrenergics,
Miscellaneous stimulants)
Leptazol and 3.8 Anti-parkinsonian drugs
Nikethamide 3.9 Narcotic analgesics &
antagonists
TESFAYE. N
 Antidepressant Drugs
Antidepressants are psychiatric drugs which are licensed to
treat depression.
If you experience depression, you may:
• feel very down a lot of the time
• no longer enjoy the things you usually enjoy
• find it hard to talk to people about how you feel
• self-harm or experience suicidal feelings, especially if you
have Severe depression.
Types of depression
• Major depression
• Chronic depression (Dysthymia)
• Atypical depression
• Bipolar disorder/Manic depression
• Seasonal depression (SAD)
TESFAYE. N
 Reversible inhibitor of MAO-A (RIMAs) A
Moclobemide ,Clorgyline N
T
• (Isocarboxacid, phenelzine, tranylcypromine.)
I
Tricyclic antideprssants (TCAs) D
E
P
 NA + 5 HT reuptake inhibitor Predominantly NA reuptake inhibitor R
Imipramine, Amitriptyline Desipramine, Nortriptyline E
Amoxapine, Reboxetine S
Trimipramine, Doxepin
Dothiepin, Clomipramine S
A
N
T
Selective serotonin Atypical antidepressants
reuptake inhibitors (SSRIs) Trazodone, Mianserine S
Fluoxetine, Fluvoxamine Mirtazapine, Venlafaxine
Paroxetine, Sertraline Duloxetine,Tianeptine
Citalopram, Escitalopram Amineptine, Bupropion
TESFAYE. N
 Amphetamines
 Amphetamines are synthetic central sympathomimetic
agent having marked CNS stimulant and anorectic effects.

 These drugs include dextro-amphetamine (d-
amphetamine) and methamphetamine.
 It acts by release of endogenous nor-adrenaline.
 Also relaxes the bronchi due to sympathetic actions.
Other CNS Stimulants
 Caffeine
 Cathine and Cathinone
 Khat
 Ephedrine
 Ritalin
TESFAYE. N
 3.8 Anti-parkinsonian Drugs
 Parkinson disease is a slowly progressive degenerative
neurologic disease
– Tremor, rigidity, sluggish neuromuscular response and
postural instability
 In Parkinsonism dopaminergic input is deficient and chloinergic
output remain unchanged

 Antiparkinsonian agents are either anticholinergic or

dopaminergic

100
TESFAYE. N
 Anticholinergics used as antiparkinsonian agents
H3C H3C H3C
N N
N
O
H CH OH H
H CH OH 2
O
2 O C CH
O C CH
O
O
Scopolamine benzotropine
Atropine

HO H2 HO H2
C C
C N C N
H2 H2

trihexyphenidyl procyclidin 101

TESFAYE. N
 Dopaminergic therapy
 Several approaches are used to eliminate dopamine deficiency
in striatum

– Augmentation of brain synthesis of dopamine

– Presynaptic dopamine release stimulation

– Direct stimulation of dopamine receptor

102
TESFAYE. N
 Cont…
1. Augmentation of dopamine synthesis
Levodopa therapy

HO NH2
HO NH2 DOPA

COOH HO
HO Decarboxylase
Dopamine
Levodopa

 Levodopa is co-administered with dopadecarboxylase inhibitors

CH3 O
CH2C NHNH2 CH2NHNHC CHCH2OH.HCl
COOH NH2
HO OH
OH
OH OH Benseriazide hydrochloride
Carbidopa
103
TESFAYE. N
 Cont…
 Another means of increasing dopamine level is inhibition of MAO-B
 Selegiline is selective inhibitor of MAO type B and prevents
breakdown of dopamine selectively
CH3
CH2CH N CH2 C CH
CH3

2. Stimulation dopamine release

 Agents that release dopamine from neuronal storage can be used
 Amantidine is an example of such drug
NH2HCl

 Amantadine increase dopamine levels at postsynaptic receptor by decreasing

presynaptic re-uptake and enhancing dopamine synthesis and release
104
TESFAYE. N
 Cont…
3. Direct Dopamine agonist
• Includes the ergot alkaloid derivatives Bromocriptine and
Pergolide
• Dopamine agonists have the advantage in that their effect is
independent of striato nigral degeneration
H3C CH3
O HC H CH2SCH3
O OH
H C NH
N H
N N
O O CH CH2CH2CH3
N CH CH 3 H
CH3 2
CH3
H
NH
HN Pergolide
Br CH3SO3H
Bromocriptine
105
TESFAYE. N
 3.9 Narcotic analgesics & antagonists

 The term 'opium alkaloids' has been used to cover all narcotic
analgesics, whether they are synthetic compounds, partially
synthetic, or extracted from plant material.
 extracted from opium—the sticky exudate obtained from the
poppy (Papaver somniferum)

 The opiates are perhaps the oldest drugs known to man.

– The use of opium was recorded in China over two
thousand years ago and was known in Mesopotamia
before that.
106
TESFAYE. N
 Cont…
 Opium contains a complex mixture of almost twenty-five
alkaloids.
– The principle alkaloid in the mixture, and the one
responsible for analgesic activity, is morphine, named after
the Roman god of sleep—Morpheus.
– Morphine was isolated commercially in 1833 and its
structure was elucidated in 1925
– It was fully synthesized in 1952

107
TESFAYE. N
 The steps involved development of narcotic analgesics

1. Recognition that a natural plant or herb (opium from the

poppy) has a pharmacological action.
2. Extraction and identification of the active principle
(morphine).
3. Synthetic studies (full synthesis and partial synthesis).

4. Structure-activity relationships—the synthesis of analogues to see

which parts of the molecule are important to biological activity.
5. Drug development—the synthesis of analogues to try and improve
activity or reduce side-effects.
6. Theories on the analgesic receptors. Synthesis of analogues to test
theories.

 Stages 5 and 6 are the most challenging and rewarding parts of

the procedure as far as the medicinal chemist is concerned.
108
TESFAYE. N
 Structure and properties of Morphine

Morphine is still one of the most effective painkillers available

to medicine.
It is especially good for treating dull, constant pain rather than
sharp, periodic pain.
side-effects of morphine include the following:
• depression of the respiratory centre • dependence
• constipation • nausea
• excitation • pupil constriction
• euphoria • tolerance
109
TESFAYE. N
 Structure-activity relationships

 The molecule contains five rings labelled A-E and has a

pronounced T shape.
 It is basic because of the tertiary amino group, but it also
contains a phenolic group, an alcohol group, an aromatic
ring, an ether bridge, and a double bond.

i. Changes which do not affect the basic skeleton of the molecule

The phenolic OH
 By methylating the phenolic OH, the analgesic activity drops
drastically and codeine is only 0.1 per cent as active as morphine.
 This drop in activity is observed in other analogues containing a
masked phenolic group.
 Clearly, a free phenolic group is crucial for analgesic activity.
110
TESFAYE. N
 Cont…

• Codeine a pro drug for morphine, it is metabolized in vivo to

morphine when it is going to be given orally
The 6-alcohol

111
TESFAYE. N
 Cont…
 General observation;
– masking or the complete loss of the alcohol group does
not decrease analgesic activity and, in fact, often has the
opposite effect.
– improvement in activity is due to the pharmacokinetic
properties of these drugs rather than their affinity for the
analgesic receptor.
– In other words it increase the amount of the drug that will
reach to the CNS
• Example compare the activities of morphine, heroine
and 6 acetyl morphine.

112
TESFAYE. N
 Cont…
The double bond at 7-8
 Several analogues including dihydromorphine (below) have shown
that the double bond is not necessary for analgesic activity.

The N-methyl group

The methyl group is not must but the nitrogen should
be there and it must be ionized.

113
TESFAYE. N
 Cont…
The aromatic ring
 The aromatic ring is essential. Compounds lacking it show no
analgesic activity.

The ether bridge

 The ether bridge is not required for analgesic activity.

Note: To sum up, the important functional groups for analgesic

activity in morphine are shown below

114
TESFAYE. N
 Development of morphine analogues
Strategies in the development of morphine analogues
• variation of substituents
• drug extension
• Simplification
• rigidification

A. Variation of substituents
– A series of alkyl chains on the phenolic group give
compounds which are inactive or poorly active.
– The removal of the N-methyl group to give normorphine
allows a series of alkyl chains to be built on the basic centre.

115
TESFAYE. N
 Cont…
B. Drug extension
 Drug extension is a strategy by which the molecule is
'extended' by the addition of extra 'binding groups'.
 The reasoning behind such a tactic is to probe for further
binding sites
 Many analogues of morphine have been made with extra
functional groups attached.
 These have rarely shown any improvement. However, there
are two exceptions.
– Introduction of hydroxyl group at 14-postions (fig. below) and
– N-substitution (most successful approach)

116
TESFAYE. N
 Cont…
Effect of N-substitution

 As the alkyl group is increased in size from a methyl to a butyl

group, the activity drops to zero

 However, with a larger group such as an amyl or a hexyl group,

activity recovers slightly.

 when a phenethyl group is attached the activity increases 14

fold—a strong indication that a hydrophobic binding site has
been located which interacts favourably with the new aromatic
ring 117
TESFAYE. N
 Cont…
 Another result by N-substituition

 Naloxone has no analgesic activity at all, whilst nalorphine retains only

weak analgesic activity
 They are given whenever there is morphine overdose
 In addition the discovery of nalorphine helps for the synthesis of other
morphine analogues with less addiction and CNS depressant activity
 This is because the difference in the type of opiate receptors in the CNS
118
TESFAYE. N
 Cont…
C. Simplification or drug dissection
 Objective-to simplify the complex structure of morphine
molecule, so that it would be easier to make it in the
laboratory
– allow the chemist to make analogues much more easily, and any
useful compounds could be made more efficiently and cheaply.

 From the five rings present in the structure of morphine,

analogues were made to see which rings could be removed

119
TESFAYE. N
 Cont…
Removing ring E
 Removing ring E leads to a complete loss of activity. This
result emphasizes the importance of the basic nitrogen to
analgesic activity.

Removing ring D
 gives a series of compounds called the morphinans which
have useful analgesic activity
 the oxygen bridge is not essential

120
TESFAYE. N
 Cont…

 Morphinans are more potent and longer acting than their

morphine counterparts, but they also have higher toxicity and
comparable dependence characteristics

 The modifications carried out on morphine, when carried out

on the morphinans, lead to the same biological results.

 The morphinans are easier to synthesize since they are simpler

molecules

121
TESFAYE. N
 Cont…
Removing rings C and D
 gives an interesting group of compounds called the benzomorphans
which are found to retain analgesic activity.
 One of the simplest of these structures is metazocine which has the
same analgesic activity as morphine

122
TESFAYE. N
 Cont…
Conclusion about benzomorphans
 Rings C and D are not essential to analgesic activity.
 Analgesia and addiction are not necessarily coexistent.
 6, 7-Benzomorphans are clinically useful compounds with
reasonable analgesic activity, less addictive liability, and less
tolerance.
 Benzomorphans are simpler to synthesize.

Removing rings B, C and D

 Removing rings B, C and D give a series of compounds known
as 4-phenylpiperidines.
 The analgesic activity of these compounds was discovered by
chance.

123
TESFAYE. N
 Cont…

 Meperidine (pethidine) is not as strong an analgesic as

morphine and also shares the same undesirable side-effects.

 However, it has a rapid onset and a shorter duration and as a

result has been used as an analgesic for difficult childbirths

 The piperidines are more easily synthesized than any of the

above groups and a large number of analogues have been
studied 124
TESFAYE. N
 Cont…
 The replacement of the methyl group of meperidine with a
cinnamic acid residue increases the activity by 30 times, where
as putting the same group on morphine eliminates activity

 One of the most successful piperidine derivatives is fentanyl

which is up to 100 times more active than morphine

125
TESFAYE. N
 Cont…
Conclusions:

• Rings C, D, and E are not essential for analgesic activity.

• Piperidines retain side-effects such as addiction and

depression of the respiratory centre.

• Piperidine analgesics are faster acting and have shorter

duration.

• The quaternary centre present in piperidines is usually

necessary (fentanyl is an exception).

• The aromatic ring and basic nitrogen are essential to activity,

but the phenol group is not.

• Piperidine analgesics appear to interact with analgesic

receptors in a different manner to previous groups.
TESFAYE. N
126
 Cont…
Removing rings B, C, D and E
 The analgesic methadone was discovered in Germany during
the Second world war

 The compound has been given to drug addicts as a substitute

for morphine (or heroin) in order to wean them off these
drugs.

127
TESFAYE. N
 Cont…
D. Rigidification
• This strategy is usually employed in an attempt to remove the
side-effects of a drug or to increase activity.

• Rigidification restricts the molecule to the specific

conformation which fits the desired receptor

• The best example of this tactic in the analgesic field is

provided by a group of compounds known as the oripavines

Oripavine
128
TESFAYE. N
 Cont…

Etorphine

Note: Why phenethyl morphine is agonist while allyl morphine is

antagonist

129
TESFAYE. N