Drugs Acting on CNS: CNSdepressants. Usedtotreatinsomnia ... · Drugs Acting on CNS: Depressant Drugs Associate Prof. Magdi A. Mohamed, Faculty of Pharmacy, University of Khartoum

Drugs Acting on CNS:

Depressant DrugsDepressant Drugs

Associate Prof. Magdi A. Mohamed, Faculty

of Pharmacy, University of Khartoum (2014)1

Sedative & Hypnotics

• CNS depressants.

• Used to treat insomnia.

• Sedatives decrease excitability but do not• Sedatives decrease excitability but do not

induce sleep.

• Hypnotics induce sleep.



• Insomnia can be classified as:

� Primary (pathogenesis unknown).

� Secondary (situational stress, lifestyle� Secondary (situational stress, lifestyle

habits, drugs, and psychiatric or medical

disorders).



Sleep Cycle

• Wakefulness.

• Nonrapid eye movement [NREM] sleep.• Nonrapid eye movement [NREM] sleep.

• Rapid eye movement [REM] sleep.



Sleep Factors

• Autonomic, physiologic, and biochemical

changes.

• Neurotransmitters:

� Catecholamines, serotonin, histamine,

acetylcholine, adenosine, γ-aminobutyricacetylcholine, adenosine, γ-aminobutyric

acid.

• Hormones:

� Growth hormone, prolactin, and

melatonin.



Sedative-Hypnotic Drugs

• Chloral hydrate.

• Barbiturates.

• Benzodiazepines.

• Nonbenzodiazepines• Nonbenzodiazepines

• Melatonin receptor agonists.

• Antihistamines.

• Antidepressants.



• The ideal sedative-hypnotic should:

� Induce and maintain sleep without

lingering effects.

� Not decrease or arrest respirations (even at



� Not decrease or arrest respirations (even at

relatively high doses).

� Produce no abuse, addiction, tolerance or

dependence.

Barbiturates

• Cyclic ureides are formed when a dicarboxylic

acid reacts with urea.



• The cyclic ureides are acidic owing to

enolization.Associate Prof. Magdi A. Mohamed, Faculty


NH

NO

O

O

OH

NH

NO

O

O

H2O

H

Na

NH

NO

O

ONa

• The cyclic ureides are acidic owing to

enolization.Associate Prof. Magdi A. Mohamed, Faculty


Parabanic acid Sodium salt ofParabanic acid

• Cyclic ureides derived from malonic acid or

malonic esters are known as barbiturates

because of their relationship with barbituric

acid (malonyl urea).Associate Prof. Magdi A. Mohamed, Faculty




• Barbituric acid does not possess any hypnotic

properties.

• To be active the hydrogen atoms at C-5 should

be replaced by organic groups (alkyl or aryl).





C

COOC2H5

COOC2H5

H

H

Diethylmalonate

R1 X

C2H5ONaC

COOC2H5

COOC2H5

H

R

MonoalkylDiethylmalonate

R2 X

C2H5ONaC

COOC2H5

COOC2H5

R2

R1

DialkylDiethylmalonate

H N C NH

OO

R1

OR1



C2H5ONa

H2N C NH2

N

NH

O NaO

1

R2

Sodium 5,5-Dialkylbarbiturate

H

NH

NH

OO

1

R2

5,5-Dialkylbarbituric acid



Classification of Barbiturates

• Long acting (6-8 hours).

• Intermediate acting (2-6 hours).

• Short acting (1-2 hours).

• Ultra-Short acting ( minutes).



Long Acting Barbiturates





Intermediate Acting Barbiturates



Short Acting Barbiturates



Ultra-Short Acting Barbiturates

2 5



2 2 3

3

Mechanism of Action of Barbiturates

• GABA is the principal inhibitory

neurotransmitter in CNS.

• Barbiturates bind to GABA-A receptors.

• Ligand-gated ion channels (Cl− influx).• Ligand-gated ion channels (Cl− influx).

• Decrease excitability (hyperpolarization).

• Barbiturates potentiate the effect of GABA at

these receptors (distinct binding site).

• …………….



Structure Activity Relationships

NH

C

HN

O O

X

1 2 3

56 4

R R

X = O or S

NH

C

N

O O

X

1 2 3

56 4

R R

X = O or S

R

hypnotic, anticonvulsant, or anesthetic activity



NH

C

HN

O O

X

1 2 3

56 4

R H

X = O or S

N

C

N

O O

X

1 2 3

56 4

H H

X = O or S

R RN

C

N

O O

X

1 2 3

56 4

R R

X = O or S

R R

hypnotic, anticonvulsant, or anesthetic activity

not active

Structure Activity Relationships: 5,5-

Disubstitution

• Lipophilic groups increase the activity of

barbiturates (to certain limit).

• Polar groups decrease the activity of

barbiturates.Associate Prof. Magdi A. Mohamed, Faculty


Structure Activity Relationships:

Substitution on Nitrogen

N

C

HN

O

O

O

R

R

R1

N

C

N

O

O

O

R

R

R1

R2

• Monosubstitution increases lipophilicity.

• Disubstitution renders barbiturates inactive.



R = CH3, C2H5, C3H7

R1

not acid

R1

Structure Activity Relationships:

Modification of Oxygen

• Replacement of C2 oxygen by sulfur increases

lipid solubility.



Metabolism of Barbiturates

N

NH

O

OO

CH3

5

(R/S)-Mephobarbital

(1)

N

NH

O

OO

CH3

5HO(2)

N

NH

O

OO

CH3

5RO

R = glucuronide and/orsulfate conjugate

(3)

NH

O

5

(1)NH

O

5HO(2)

NH

O

5RO

R/S = 6.9



N OO

H

phenobarbital

N OO

H

N OO

H

R = glucuronide and/orsulfate conjugate

(2)

N

NH

O

OO

5

O

HO2C

OH

OHOH

H

glucuronide conjugate

S/R = 6.8

Benzodiazepines

N

N

O

Cl

NEt2

F

N

N

S

Cl

CF3

F

N

NCl

Cl

NNCH3

N

NCl

NN



Flurazepam Quazepam Triazolam Estazolam

Nitrazepam

HN

N

O

O2N

Temazepam

N

N

OCH3

Cl

OH

Nonbenzodiazepines (Z compounds)



Metabolism of the Z Compounds

N

N N

CN

N

CH3

CH3

O

Zaleplon

minorpathway

N

N N

CN

HN CH3

O

NH

N N

CN

N

CH3

CH3

O

majorpathway

O



N

N

H2C

CH3

N

O

H3C

CH3

minor

N

N

C

CH3

N

O

H3C

CH3OH

O

OH

N

N

H3C

CH3

O N

N

H3C

CH3

O

HO

majorpathway

majorpathway



pathway3

N

H3C

CH3

N

N

H3C

CH2OH

N

O

H3C

CH3

Zolpidem

3

N

H3C

CH3

majorpathway

majorpathway

N

N

H3C

C

N

O

H3C

CH3

O

OH

Melatonin Receptor Agonists

NH

CH3O

HN

CH3

O

Melatonin

• Hormone of darkness.

• Synthesized in the pineal gland.

• Secreted during the night.

• Used to alleviate jet lag.



N-acetyl-5-methoxytryptamine

Melatonin Receptor Agonists

• Poor absorption.

• Low oral bioavailability.

• Rapid first-pass metabolism to 6-

hydroxymelatonin (its primary metabolite).



Design of Ramelteon

• Ramelteon (Rozerem®, FDA approved in 2005)

as a very potent and very selective ligand for

MT1 receptor, with superior in vivo activity

and safety profile for use in the treatment of

insomnia.Associate Prof. Magdi A. Mohamed, Faculty


Design of Ramelteon (Rozerem®)

• Rational Drug Design:

� Ligand-Based Drug Design.

� Structure-Based Drug Design.




• The indole ring was converted into an indane

ring bio-isostere of melatonin.

• 5-Methoxy conformation!!

• Stereochemistry!!




• Conformational flexibility of the 5-methoxy

group!!





group!!





group!!




Angular

indeno[5,4-b]furan

Linear

indeno[5,6-b]furan

• The linear isomer has approximately 15000

fold weaker affinity for the MT1 receptor than

the angular one.

• Binding of nonbonding oxygen pairs to a

histidine residue in the receptor (Mol. Mod.).Associate Prof. Magdi A. Mohamed, Faculty


indeno[5,4-b]furan indeno[5,6-b]furan








• Stereochemistry!!


Ramelteon

• The S-enantiomer of indeno[5,4-b]furan

showed approximately 500 fold greater

affinity than the R-isomer for MT1 receptor.



Ramelteon

Synthesis of (S)-Ramelteon



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Drugs Acting on CNS: CNSdepressants. Usedtotreatinsomnia ... · Drugs Acting on CNS: Depressant Drugs Associate Prof. Magdi A. Mohamed, Faculty of Pharmacy, University of Khartoum