H01043 Hoá Dư C 2 Lecture 8 Antipsychotic Drugs

Lecture 5
Drugs affecting central nervous system
Antipsychotic drugs
Phuong-Thuy Thi PHAN, M.S.
Recommended Reading
1) Beale, J.M., Block, J.H. (2011). Wilson and Gisvold’s Textbook
of Organic Medicinal and Pharmaceutical Chemistry 12th edition,
Lippincott Williams & Wilkins: Baltimore. Chapter 12. Central nervous
system depressants, p.p. 443-470.
2) Beale, J.M., Block, J.H. (2011). Wilson and Gisvold’s Textbook

of Organic Medicinal and Pharmaceutical 12th edition,
Lippincott Chemistry Williams & Wilkins: 13.
dopaminergic
Baltimore.Chapter
signaling agents, p.p. 471-490. Central
3) Thomas L.L., David A.W. (2013). Foye’s Principle of

Medicinal Chemistry 7th edition, Lippincott Williams &
Wilkins: 14.
Chapter Baltimore.
Antipsychotic and anxiolytic drugs, p.p. 438-484.
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H01043-LECTURE 8-ANTIPSYCHOTIC DRUGS
Goals
1) Indentify the structural features of antipsychotic drugs
2) Describe the SAR of phenothiazines and related analogs
3) Know the background information of antipsychotic drugs
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Psychotic disorders
 Disorders that feature:

• Failures of reality testing
• Creation of new realities
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Phenothiazines - Structure
EWGs increase D2 potency
3- atom chain between 2 Ns is optimal
Amine is always tertiary
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Phenothiazines - Conformation of side chain
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Phenothiazines - Conformation of phenothiazine ring
Butterfly conformation Twisted conformation

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Allosteric
site binding
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Phenothiazines - SAR
 Ring substitutions
• Electron withdrawing groups (X) enhance activity
5
• More than one substitution on the ring system decreases potency 6
S
4
7 3
• The most potent position for the electron withdrawing group is C2 C B A

10 2
8
N X
9 1
which may help bending the side chain N through H bond to form
 
dopamine-like conformation
 R1
• The rank order of potency is position 2>3>4>1 N
R2
• Stronger electron withdrawers are more potent (exception
may
apply)
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CH3
CH3
H3 C CH3
H CH3 CH3 CH3 CH3 CH3 CF3 N CF3
CH2
O H O O C O S O Cl S O S O S O O S O CF3
CH2 S
O C
CH2
Least potent
CH3 O C Most potent
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 Alkyl side chain
5
• Increasing or decreasing the length from 3 carbons decreases 6
S
4
7 3
C B A
the potency. Two carbon side chains increase H1 8
10 2
• antagonism
N X
Substituents on the ɤ carbon decrease 9 1
 
dopamine antagonism
R1
but increase anticholinergic activity. These 
N
would be expected to R2
produce less extrapyramidal side effects. All the piperidines fit
this category
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 Substituents on the ɤ nitrogen
• Dimethyl substitution on the ɤ nitrogen: Names are ending by “-
promazine”; The prefix depends on the C2 substituent
• Incorporation of the ɤ nitrogen into a 2-piperidine ring: They are
named ending with “-ridazine”; The prefix depends on the C2
substituent
• Incorporation of the ɤ nitrogen into a piperazine ring: They are
named as follows: If the para nitrogen has a methyl ending by “-
perazine”; If the para nitrogen has a hydroxyethyl ending by “-
phenazine”; The prefix depends on the C2 substituent
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 Substituents on the ɤ nitrogen
• The order of potency based on ɤ N substitution is:
piperazine >
aliphatic > piperidine
• Piperidine: The ɤ carbon branching lowers D2 affinity such that these
have the lowest potency of the three classes of phenothiazines.

However they increase M & H1 affinity
• Piperazine: Rings with substituents are more potent than those
without. Hydroxyethyl substituents are more potent than a methyl
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 Potency comparison
• Potency at the D2 receptors: Given substituents - Piperazine >
equal C2 Aliphatic > Piperidine
• Extrapyramidal side effects: Piperazine > Aliphatic > Piperidine
• Anticholinergic potency: Piperidine > Aliphatic > Piperazine
• Sedation: Piperidine > Aliphatic > Piperazine
• α receptor antagonism: Aliphatic > Piperidine > Piperazine
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Name R10 X Effect
Chlorpromazine
Thioridazine
Mesoridazine
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Name X Effect
R10
Prochlorperazine
Trifluoperazine
Perphenazine
Fluphenazine
Fluphenazine deconate
5/8/2020 H01043-LECTURE 8-ANTIPSYCHOTIC DRUGS 16
First generation antipsychotic drugs
Thioxanthenes
• 2 fused benzenes flaking S in 6 mem.ring
• Z (cis) isomer is more potent (5-40x) which most marketed

drugs are
Fluorobutyrophenones A ring Basiz 3o

amine
with EWG
• F - 4C chain - phenyl - ketone
Alkyl side
• High D2 potency with anticholinergic chain
little
effects
• HPP+ metabolite: neurotoxicity
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Second generation antipsychotic drugs
Dibenzoxazepines
• 2 fused benzenes - O - N - 7 mem. ring
• High affinity for D2 receptor
Dibenzothiazepines
• 2 fused benzenes - S - N - 7 mem. ring
• Low affinity for D2 receptor
• Moderate affinity for D4 receptor
• High affinity for 5-HT2A, M & H1 receptor
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Dibenzodiazepines
• 2 fused benzenes - 2N - 7 mem. ring
• Low affinity for D2 receptor
• Moderate affinity for D4 receptor
Dibenzoxepines
• 2 fused benzenes - O - 7 mem. ring
• High affinity for 5-HT2A, H1 & α1 receptor
• Partial D2 agonist
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Dihydrocarbostyrils
• Aryl - piperazine - quinolinone
• High affinity for 5-HT2A, α1 receptor
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Benzisoxazoles
• Aryl - piperidine - benzisoxazole
• High affinity for 5-HT2A, α & H1 receptor
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Benzisothiazoles
• Aryl - piperidine - benzisothiazole
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Pimvanserin
• High affinity for 5-HT2A
• Very little D2 affinity
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Homework
1. What ring geometry favors antipsychotic and antidepressant activities and why?
2. Why phenothiazines are antagonists to dopamine receptro? Explain the binding modes.
3. What is the effect of ring substitution on antipsychotic potency? Know about both type and
position of substitution.
4. What type of side chain favors the antipsychotic activity and antihistaminic activity? What is
the effect on branching the side chain on both antihistaminic and antipsychotic effect?
5. What are different types of amine functions on the side chain? Compare their antipsychotic
and othar effects of all three types of amines – the aliphatic, piperidine and piperazine.
6. What are thiothexenes and their activities? Activity difference of loxapine and amoxapine.
7. What are atypical antipsychotics? Why do they not possess extrapyramidal side effects?
8. Identify the atypical drugs from group of structures. How was ziprasidone developed?
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H01043 Hoá Dư C 2 Lecture 8 Antipsychotic Drugs

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Lecture 5

Drugs affecting central nervous system

2) Beale, J.M., Block, J.H. (2011). Wilson and Gisvold’s Textbook

3) Thomas L.L., David A.W. (2013). Foye’s Principle of

2) Describe the SAR of phenothiazines and related analogs

3) Know the background information of antipsychotic drugs

 Disorders that feature:

EWGs increase D2 potency

3- atom chain between 2 Ns is optimal

Amine is always tertiary

Butterfly conformation Twisted conformation

• The most potent position for the electron withdrawing group is C2 C B A

have the lowest potency of the three classes of phenothiazines.

• Extrapyramidal side effects: Piperazine > Aliphatic > Piperidine

• Anticholinergic potency: Piperidine > Aliphatic > Piperazine

• Sedation: Piperidine > Aliphatic > Piperazine

• α receptor antagonism: Aliphatic > Piperidine > Piperazine

• Z (cis) isomer is more potent (5-40x) which most marketed

Fluorobutyrophenones A ring Basiz 3o

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