Medicinal chemistry

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Hypnotics

(Non-rapid eye movement, NonREM sleep)

(Rapid eye movement, REM sleep)

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4

Hypnotics
Barbiturates
Benzodiazepines
Aldehydes

Barbiturates

Barbituric acid
Tautomerization

Barbiturates

5 alkyl aryl

Carbon Chain
2 S

1 CH3

Benzodiazepines

Benzodiazepines Benzodiazepine receptor

GABA

GABA GABA receptor Cl- ion channel

GABA- Benzodiazepine-chloride ionophore complex

Benzodiazepines

R1 electron withdrawing group

R2 Alkyl group C
R3 Alkyl group
Polar (-OH, -COOH)
Phenyl group
Halogen (F, Cl, Br, I)
ortho phenyl group

Benzodiazepines
Long acting
t > 48

Chlordiazepoxide

Diazepam

Flurazepam

Benzodiazepines
Intermediate acting
t 24-48

Clonazepam

Nitrazepam

Flunitrazepam

Benzodiazepines
Short acting
t 12-24

Lorazepam

Oxazepam

Temazepam

Benzodiazepines
Ultra short acting
t < 12

Alprazopam

Midazolam

Triazolam

Benzodiazepines
t 6-20 hr

t > 20 hr

t 36-96 hr
t < 6 hr

long acting
Alprazopam
Active
metabolite t

Midazolam

Triazolam

Aldehydes
Chloral hydrate

Metabolize active metabolite
Trichloroethanol (TCE) glucuronidation

Antidepressants
(Depression)

10%

:
: Monoamines
(Serotonin, Catecholamines; norepinephrine dopamine)

Antidepressants
Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin norepinephrine reuptake inhibitors (SNRIs)

Tricyclic antidepressants (TCAs)

10

11

3 ring molecular core

Amines

Chain Carbon atom 4

N
R2
Potency is in order
3 > 2 > 1 amine

R1

Nitrogen alkyl groups Methyl

loss activity toxicity
3o Amines
serotonin transporter
Greater anticholinergic
Greater antihistaminergic
2o Amines NE transporter

Tricyclic antidepressants (TCAs)

Non-selective blockade of Norepinephrine and Serotonin reuptake

Other Pharmacology

Antagonism of Biogenic Catecholamine (NE,5-HT) Reuptake

Antagonism of Alpha-1 Adrenergic Receptors

Hypotension vasoconstriction reflex Tachycardia

Antagonism of M2 Receptors

CNS Depression
Peripheral NE blockade Beta-1 Adrenergic Receptors

Antagonism of H1 Histamine Receptors

Sedation

Tricyclic antidepressants (TCAs)

Amitriptyline
3o Amine

Nortriptyline
2o Amine

Nortriptyline active metabolite Amitriptyline

Nortriptyline sedative

Monoamine oxidase inhibitors

(MAOIs)
enzyme Monoamine oxidase catecholamines

TCAs MAOIs 10 Drug
interaction

H
N

NH2

H
N

NH2

N
H

Phenelzine
Benzene Ring substitution
N substitution
free hydrogen 1 Nitrogen atom

H
N

O
CH3

Isocarboxazide

Selective serotonin reuptake

inhibitors (SSRIs)

reuptake serotonin serotonin

NE Dopamine
histamine & cholinergic receptor
Fluoxetine
Citalopram and Paroxetine are potent and most specific SSRIs

Paroxetine

Citalopram

Escitalopram

Serotonin norepinephrine reuptake

inhibitors (SNRIs)
reuptake serotonin norepinephrine
Duloxetine Fibromyalgia

Venlafaxine

Desvenlafaxine

Duloxetine

Antipsychotic drugs
Dopamine limbic cortex

(Schizophrenia)

: amphetamine

Antipsychotic drugs
Phenothiazines
Atypical Antipsychotics

First-generation (butyrophenones)
Second-generation (clozapine, risperidone)

Phenothiazines

2 H 10
aliphatic side chain

EPS

3o Amines BBB

Promazine
X=H

Chlorpromazine
X=Cl

Triflupromazine
X=CF3

Phenothiazines

Thioridazine

Perphenazine

H 10
piperidine side chain

EPS
ANS : Anticholinergic effect

H 10
piperazine side chain

EPS
ANS : Anticholinergic effect

Phenothiazines

Butyrophenones
C=O (ketone)
Carbon chain 4 atom (butyl)

antipsychotic activity
Basic nitrogen six-membered ring
Aromatic ring 4 six-membered ring

EPS

Dibenzazepines

Clozapine

Olanzapine

Quetiapine

Risperidone
benzisoxazole derivative high affinity central serotonergic
5-HT2, dopaminergic D2 adrenergic 1-receptors
positive (delusions, hallucinations)
negative (diminished emotions, low motivation) symptoms
schizophrenia EPS