Antipsychotics

There is no cure for Schizophrenia

just symptomatic control is done
 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
 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
.
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
 Major Dopamine pathways
Pathway Significance Associated disease
The Nigro-straital Movement Low dopamine causes
pathway EPS (Extra Pyramidal
symptoms)
The Mesocortical Motivation, pleasure, High Dopamine causes
pathway socialization negative symptoms of
schizophrenia
The Mesolimbic Speech, grasp of High dopamine causes
pathway reality positive symptoms of
schizophrenia
The Tubero Prolactin Hormone Prolactin Hormone
infundibular pathway release deficiency

Ideally we would want dopamine blockade only in Mesocortical and

Mesolimbic pathway but that has not been realized till now
 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)
Other Neurotransmitters also have their own pathways
and unique function associated with it
• 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
 Understanding Inverse Agonism
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
• Inverse Agonist produce negative response
 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
P
o
t
e
n
c
y
Discovery of Butyrophenones
 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
O

F C CH2 N A
3
O

C CH2 N B
3
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

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)
 Diphenylbutylpiperidines
The keto group has been replaced with para Fluro group
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.
O R1

F C CH2 N
n
R2
only n= 3 is active
O R1

F C N

no cyclic form allowed R2

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
•R is always amine
•Amine is always teritary
•It can be para P
substituted for better o
t
potency or lower toxicity 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
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
 Haloperidol synthesis
O

Cl CH2CH2CH2 C Cl F

4-Chlorobutyryl -HCl
Chloride
Fluorobenzene

HO O

Cl NH Cl CH2CH2CH2 C F

4-(p-Chlorophenyl)-4-piperidionol 4-Chloro-4-fluorobutyrophenone

-HCl
O
HO

Cl N CH2CH2CH2 C F

Haloperidol
SAR of Phenothiazines
 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
2) C2 must have an electrowithdrawing group.
The activity for these various group is as
X = - SO2NR2 > -CF3 > -CO-CH3 > -Cl
Electron Donating Electron Withdrawing
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
•Esterification of the OH containing piperazine
derivatives extensively increases the duration of action
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
 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
 Chlorpromazine synthesis
H

N Cl
CH3

Cl CH2 CH2 CH2 N

CH3
S
3-Chloropropyl-dimethylamine
2-Chlorophenothiazine
Refulx
in presence of
toulene and
sodamide
CH3

CH2 CH2 CH2 N

CH3
N Cl

Chloropromazine
S
 R1 R2 R1

R2

Trans has R groups on Cis has R groups on

opposite side of double bond same side of double bond

Decide cis and trans in these compounds?

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
 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
 Schizophrenia vs Dementia
Schizophrenia Dementia
Both Positive and Negative multiple cognitive
symptoms MUST occur problems occur

Schizophrenia is It is a physiological result

independent disease of an illness or substance
eg Dementia in Parkinson
and Alzheimer
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
 Aromaticity

Which one of these tricyclic rings is

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

Antipsychotic Drugs can make you fat.

So fat that it can kill you!!!

Neuropsychiatric Disease and Treatment 2008:4(1)

 • 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)
 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?
• 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.
 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
 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
 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?