Lecture Notes for B. Pharm, Medicinal Chemistry of Purbanchal University Nepal regarding Antiphycotics

1. Antipsychotics
There is no cure for Schizophrenia
just symptomatic control is done

2. Schizophrenia
• A mental disorder where person can’t grasp reality and
shows behavioral and cognitive dysfunction
• Positive symptoms: abnormality of normal function
leading to presence of inappropriate behaviors –
Delusions (false belief)and hallucination (false
perception), speech disturbances
• Negative symptoms: loss of normal function leading to
absence of appropriate behaviors – lack of motivation,
social withdrawal, lack of interest in fun activity, doesn’t
respond to questions
SCHIZOPHRENIA IS FOR LIFE

3. Causes
We don’t know the exact cause but it is believed that
excess of dopamine activity is the reason for the
disease
The evidence for this is-
• 1st Drugs for psychosis was Chlorpromazine and it
is a D2 antagonists
• Antiphycotic drugs produce Parkinson-like
symptoms
• Drugs that promote dopamine activity, L-Dopa and
amphetamine, produce or increase Schizophrenia
• There is increase in number of brain dopamine
receptor
.

4. Counter evidence of the dopamine hypothesis
• Older drugs are not effective in all patients
• Newer atypical drugs low affinity for
dopamine receptors
• Drugs that block NMDA produce more
Schizophrenia than even drugs that promote
dopamine
This suggests other NT than dopamine is also
involved

5. Major Dopamine pathways
Pathway Significance Associated disease
The Nigro-straital
pathway
Movement Low dopamine causes
EPS (Extra Pyramidal
symptoms)
The Mesocortical
pathway
Motivation, pleasure,
socialization
High Dopamine causes
negative symptoms of
schizophrenia
The Mesolimbic
pathway
Speech, grasp of
reality
High dopamine causes
positive symptoms of
schizophrenia
The Tubero
infundibular pathway
Prolactin Hormone
release
Prolactin Hormone
deficiency
Ideally we would want dopamine blockade only in Mesocortical and
Mesolimbic pathway but that has not been realized till now

6. Dopamine and EPS
• We studied in Parkinson that Dopamine is a
Neurotransmitter (NT) involved in movement (in
balance with acetylcholine)
• When dopamine levels decreases, due to action
of antipsychotic drugs in all Dopamine pathways,
movement related disorders called Extra
Pyramidal symptoms (EPS) arise which includes
– akinesia (inability to initiate movement) and
– akathisia (inability to remain motionless) and
– acute dystonia (twisting of muscles)

8. Other Neurotransmitters also have their own pathways
and unique function associated with it

9. • DOPAMINE RECEPTORS
Receptor 2o Messenger System
D1 cAMP
D5 cAMP
D2* cAMP,
D3 cAMP,
D4 cAMP
*Most antiphycotic drugs antagonize or inverse
agonize block D2 but newer atypical drugs have
other mechanism too based on acetylcholine,
histamine, serotonin, adrenaline

10. Ideally receptor are silent or non-functional
without being bound by their natural agonist.
But some receptor are active even when they are not
bound by any agonist. In this case inverse agonists
work to produce opposite response.
Inverse agonism is a property seen in only those
receptors (not enzymes) that are active even
without any binding to their agonist/ligand/substrate.
Ref: Continuing Education in Anaesthesia, Critical Care & Pain | Volume 4 Number
6, page 181-184 2004
Understanding Inverse Agonism

11. • Inverse Agonist produce negative response

12. Classification
1st Gen/Typical: High affinity for Dopamine receptor and
consequently have Extra Pyramidal symptoms (EPS)
• Butyrophenones: Haloperidol*, Droperidol
• Phenothiazines
– Aliphatic : Chlorpromazine*, Trifluopromazine
– Piperidine : Thioridazine, Piperacetazine
– Piperizine : Fluphenazine, Perfenazine
• Thioxanthines: Flupenthixol, Thiothixene
2nd Gen/Atypical: They primarily affect other NT but for
exact reason have a wide Side effect profile including
obesity
• Olanzapine, Quetiapine,
• Aripiprazole, Risperidone

13. P
o
t
e
n
c
y

14. Discovery of Butyrophenones

15. SAR of Butyrophenones
1) Modification of benzoyl group
• Anything other than fluorine in the para
position lowers activity
• A is 4 times more potent than B due to F
C
O
CH2 N
3
F
C
O
CH2 N
3
A
B

16. 2) Replacing the carbonyl group with isoteric
group or any other functional group lowers
activity
X can’t be N or S or C X can’t be OH, NH2, SH

17. An important exception - Diphenylbutylpiperidines
Replacement of the carbonyl of haloperidol with
para fluro phenyl group creates a new class of
compounds called diphenylbutylpiperidines that
has following advantage
–Long acting
–NO sedative, autonomic, extrapyrimidal
side effects
–Useful in autism (Autism is a mental
disorder in children characterized by
impaired social interaction and verbal and
non-verbal communication, and by
repetitive behavior)

18. Diphenylbutylpiperidines
The keto group has been replaced with para Fluro group

19. 3) Modification of the -CH2- linker group
The linker has to be a propylene. Any alteration
to the -CH2- linker region such as shortening,
lengthening, branching, or incorporation into
a ring system, results in a marked decrease or
even complete loss of neuroleptic activity.
C
O
CH2 N
n
F
only n= 3 is active
R2
R1
NC
O
F
R1
R2no cyclic form allowed

20. 4) Modification of the amino group
a) A tertiary amino group should be present
b) A tertiary amine in some cyclic form
(piperidine, tetrahydropyridine or piperazine
ring) increases potency
c) Further modification of the ring at para
position can de done for better potency and
reducing toxicity

21. P
o
t
e
n
c
y
Ref:Paul A. J. Janssen, Willem F. M. Van Bever
Structure-Activity Relationships of the Butyrophenones and Diphenylbutylpiperidines
Handbook of Psychopharmacology,1978, pp 1-35
•R is always amine
•Amine is always teritary
•It can be para
substituted for better
potency or lower toxicity

22. Haloperidol
• It is a Butyrophenone derivative used in the treatment
of schizophrenia and delirium
• It has High incidences of Extra Pyrimidal Side
efects(EPS – tremor and motor dysfunction) but Low
hypotension and low autonomic side effects
and sedative effects lower than Chlorpromazine
• Decanoate Esterifation at the OH group forms a long
acting derivative
• MOA- It is an inverse agonist in Dopamine D2 receptor
in the Mesocortical and Mesolimbic pathway
Ref: British Journal of Pharmacology (1997)
121,731± 736

23. Haloperidol synthesis
CH2CH2CH2Cl C
O
Cl F
CH2CH2CH2Cl C
O
F
4-Chlorobutyryl
Chloride
Fluorobenzene
4-Chloro-4-fluorobutyrophenone
-HCl
Cl NH
HO
4-(p-Chlorophenyl)-4-piperidionol
Cl N
HO
CH2CH2CH2 C
O
F
-HCl
Haloperidol

24. SAR of Phenothiazines

25. SAR of Phenothiazines
1) Unsubstituted Phenothiazines has no activity
but has enough lipophilicity for good brain
penetration.
Substitution at C2 and N10 is required for
activtiy

26. 2) C2 must have an electrowithdrawing group.
The activity for these various group is as
X = - SO2NR2 > -CF3 > -CO-CH3 > -Cl

27. Electron Donating Electron Withdrawing

28. 3) A terminal amino substituent must be
present at N10. It can be piperazine,
piperidine or aliphatic and their intensity
could be ranked as follows: piperazine group
>piperidine group > aliphatic chain

29. •Esterification of the OH containing piperazine
derivatives extensively increases the duration of action

30. 4) There must be an linear (ie unbranched) alkyl
linker between the core ring and the terminal
amino ring those length is optimum at three
methylene units ie CH2-CH2-CH2
Reduction of these carbon number changes
receptor affinity

31. Chlorpromazine
• It is a phenothiazine derivative used in treatment
of schizophrenia. It was the first antiphycotic drug
• It’s also used as antiemetic and against hippcup
• Has high incidence of Extra Pyramidal side effects
• It’s metabolite has strong antiadrenergic, weak
anticholinergic and slight antihistaminergic and
antiserotonergic properties (not parent molecule)
• MOA: It antagonizes Dopamine D2 in the the
Mesocortical and Mesolimbic pathway

32. Chlorpromazine synthesis
S
N Cl
H
Cl CH2 CH2 CH2 N
CH3
CH3
3-Chloropropyl-dimethylamine
2-Chlorophenothiazine
Refulx
in presence of
toulene and
sodamide
S
N Cl
CH2 CH2 CH2 N
CH3
CH3
Chloropromazine

33. R1
R2
R1R2
Trans has R groups on
opposite side of double bond
Cis has R groups on
same side of double bond
Decide cis and trans in these compounds?

34. Flupenthixol
• It is a Thioxanthine derivative used for
treatment of schizophrenia
• It can exist in cis and trans form and only cis is
active because it mimics the conformation of
Dopamine
• It’s duration of action is long (2-3 weeks) and
hence useful in patients who have a poor
compliance with medication
MOA- It is nonselective and antagonizes both Dopamine
D1 and D2 in the the Mesocortical and Mesolimbic
pathway

35. Olanzapine
• It is an atypical drug used for treatment of
of schizophrenia and also used in bipolar disorder
• Olanzapine is a potent antagonist of the muscarinic M3
receptor and this has been linked to it’s diabetic side
effect
• It can cause heart failure, sudden death, or pneumonia
when used in older adults suffering from dementia
• MOA: It has low antagonist activity in Dopamine D2
receptor and primary action is believed to have
occurred through inverse agonism at Serotonin 5HT2A
and antagonism at adrenergic receptors

36. Schizophrenia vs Dementia
Schizophrenia Dementia
Both Positive and Negative
symptoms MUST occur
multiple cognitive
problems occur
Schizophrenia is
independent disease
It is a physiological result
of an illness or substance
eg Dementia in Parkinson
and Alzheimer

37. Quetiapine
• It is a short-acting atypical antipsychotic used for
the treatment of schizophrenia and bipolar
disorder
• It is a dopamine, serotonin, and adrenergic
antagonist, and a potent antihistamine with
negligible anticholinergic properties.
• MOA: It has low antagonist activity in Dopamine
D2 receptor and primary action is believed to
have occurred through antagonism at both
Serotonin 5HT2A and adrenergic receptors

38. Aromaticity
Which one of these tricyclic rings is
flat?

39. Aripiprazole
• It is a atypical antipsychotics used in the
treatment of schizophrenia, bipolar disorder,
irritability associated with autism and as an
adjunct in depression
• Extra Pyramidal Side effects is low
• It agonizes 5HT2C also which control satiety. Thus
this drug does not cause weight gain which is
seen with other antiphycotic drug
• MOA: It is a partial agonist at both Dopamine D2
and Serotonergic 5HT2A receptors

40. Drug Dopamine (D2) Serotonin (5HT2A) Adrenergic
Haloperidol Inverse
agonist
No action by
1st Gen
No action by
1st Gen
Chlorpromazine Antagonist No action by
1st Gen
No action by
1st Gen
Flupenthixol Both D1 & D2
antagonist
No action by
1st Gen
No actionby
1st Gen
Olanzapine Weak
Antagonist
Inverse agonist Antagonism
Quetiapine Weak
Antagonist
Antagonist Antagonist
Aripiprazole Partial agonist Partial agonist -
Summary: The MOA of antipsychotic
Drugs are not the same

41. THANK YOU

42. Revision
Special topic
Antipsychotic Drugs can make you fat.
So fat that it can kill you!!!
Neuropsychiatric Disease and Treatment 2008:4(1)

43. • People suffering from schizophrenia, on
average, die about 25 years earlier than
individuals from the general population.
• Some of this reduced life expectancy is due to
Coronary heart disease (CHD) which is turn is
due to high cholesterol due to obesity
Ref: Focal Point: Youth, Young Adults, & Mental Health. Healthy Body - Healthy Mind, Summer
2012, 26(1)

44. Antipsychotic drugs increases appetite
You become fat
Arteriole wall are squeezed by fat deposition
Coronary Heart Disease
Question is how does antipsychotic drugs make you
fat?

45. • Research led to finding that activation of
TGFβ1/SMAD3 signaling pathway led to
obesity based side effects
• Blockade of SMAD3 was speculated to counter
obesity
• Mouse who has their SMAD3 knocked out
(alteration in their DNA so that no SMAD3 is
produced by body naturally) did not become
diet induced fat*
• Also, the antiphycotic action and obesity
action were completely independent from
each other.
* Ref: Protection from obesity and diabetes by blockade of TGF-β/
Smad3 signaling Cell Metab. 2011 July 6; 14(1): 67–79.

46. Antiphycotic drugs
Activate SMAD3
Activate PPAR
Activate Adipogenesis (increase in fat cells)
This is how antipsychotic drugs and obesity are
connected
Ref: Getting ‘Smad’ about obesity and diabetes. Nutrition and Diabetes (2012)2, e29

47. It means
• It is possible to create antiphycotics drugs that
DO NOT cause obesity (ie enhance selectivity
to avoid SMAD3 receptor blockage)
• SMAD3 can be a new independent target to
reduce obesity
Lesson to learn: Pharmacology is a cool subject
• The side effects of antipsychotics drugs was
investigated and a good target for completely
different diseases was established

48. 2.5 marks questions
1. How do atypical antipsychotic drugs differ
from typical ones?
2. What is the meaning of positive and negative
symptoms of Schizophrenia?
3. How antipsychotic drugs cause Parkinson?
4. What is unique about Aripiprazole in context
of obesity?