This document summarizes the structure-activity relationship (SAR) of phenothiazine drugs. It states that the best position for substitution is at the 2-position, as electron-withdrawing groups at this position increase antipsychotic activity. A three-carbon chain between positions 10 and the amino nitrogen is important for neuroleptic activity. The amino group must be tertiary and a terminal amino substituent is required at position N10. The significance is that the protonated amino group forms hydrogen bonds with the 2-substituent in a dopamine-like arrangement, allowing competitive antagonism of dopamine receptors to treat psychoses.

1. SAR OF PHENOTHIAZINE
SIRAJUDDIN MOLLA (B. PHARMACY)
ROLL NO. 27701918043
3RD YEAR, 5TH SEM

2. Phenothiazine
Introduction..
 tricyclic structure (6-6-6 system)
 two benzene rings are linked by
a sulfur and a nitrogen atom.

3.  Unsubstituted Phenothiazines has
no activity but has enough
lipophilicity for good brain
penetration.
 Substitution at C-2 and N-10 is
required for activity
Structure Activity Relationship (SAR)

4. Deleteriou
s effect Increase
Activity
But less than
2nd position
Receptor
binding
3C chain is
important for
neuroleptic
activity
H-bonding
Between EWG
and H-atom of
protonated
amine
Phenothiazine
EWG
Increase
antipsychotic
activity
SAR….

5. SAR….
 The best position for substitution is the 2- position.
 Another possibly important structural feature in the
more potent compounds is the presence of an unshared
unshared electron pair on an atom or atoms of the 2-
substituent.
 Activity increases (with some exceptions) as electron-
withdrawing ability of the 2-substituent increases (e.g.,
chlorpromazine vs. promazine).
chlorpromazine promazine

6.  Substitution at the 3-position can improve
activity over non-substituted compounds but not as
significantly as substitution at the 2-position.
 Substitution at position 1 has a deleterious effect on
antipsychotic activity, as does (to a lesser extent)
substitution at the 4-position.
 The substituent at the 1-position might be to interfere
interfere with the side chain’s ability to bring the
protonated amino group in proximity with the 2-
substituent.
 The sulfur atom at position 5, is in a position analogous
analogous to the p-hydroxyl group of DA, and it has a
receptor-binding function.
 A substituent at position 4 might interfere with receptor
receptor binding by the sulfur atom.
SAR….
Dopamine

7.  The three-carbon chain between position 10 and the aliphatic
amino nitrogen is critical for neuroleptic activity.
 Shortening or lengthening the chain, drastically decreases the activity.
 The three-atom chain length may be necessary to bring the
protonated amino nitrogen in proximity with the 2-substituent.
 Shortening the chain to two carbons has the effect of amplifying the
antihistaminic and anticholinergic activities.
 For example, promethazine is effective antihistamine, whereas the
amino ethyl derivatives diethazine (anticholinergic) and
ethopropazine (antimuscarinic) have proved useful in the treatment of
Parkinson disease (lack of DA).
SAR….

8. SAR….
 The amine is always tertiary. N-dealkylation of the side
chain or increasing the size of amino N-alkyl
substituents reduces antidopaminergic and
antipsychotic activity.
 Decreases in size from a dimethylamino group to a
monomethylamino group, greatly decrease activity,
and also decrease activity when the size increases,
such as the one that occurs with N,N-diethylamino
group.
 So fundamental requirement of an effective size of
about that equivalent to a dimethylamino should to be
be maintained,

9.  A terminal amino substituent must be present at N10. It can be
piperazine, piperidine or aliphatic and their intensity is as
piperazine group >piperidine group > aliphatic chain
SAR….

10. Significance…
 The significance of these substituent is that the hydrogen atom of the protonated
amino group of the side chain forms H-bonds with an electron pair of an atom of the
2-substituent to develop a DA-like arrangement.
 Horn and Snyder, from x-ray crystallography, proposed that the chlorine-substituted
ring of chlorpromazine base could be superimposed on the aromatic ring of DA
(dopamine)base, with the sulfur atom aligned with the p-hydroxyl group of DA and
the aliphatic amino groups of the two compounds also aligned.
 This has long been taken to suggest that a precise fit (i.e., receptor site occupancy) is
involved in the action of these compounds.

11. MOA
 Neuroleptic disorder, or thought disorders (psychoses),
most notably the schizophrenias occurs due to
overproduction and overactivity of DA (dopamine)
 The action of these agents, competitive antagonism of DA
at D2 or occasionally D3 or D4 receptors in the limbic
system.
 Although the actual structural or anatomical lesions are not
not known, the basic defect appears to involve overactivity

12. Importance..
Antipsychotic drugs—also known as
neuroleptic drugs,
antischizophrenic drugs,
or major tranquilizers
—are used in the symptomatic
treatment of thought disorders
(psychoses), most notably the
schizophrenias.

13. Reference
1. Wilson and Giswold’s Organic medicinal and
Pharmaceutical Chemistry.
2. Foye’s Principles of Medicinal Chemistry.