5. DOPAMINE RECEPTOR
Anionic site on receptor to
interact with the protonated
nitrogen of dopamine
A flat, hydrophobic area
that interacts with the
phenyl ring and hydrogen
bonding at specific areas
around the phenyl ring to
accommodate the ring
hydroxyls
A two carbon distance
between the anionic site and
the ring site
7. PHENOTHIAZINE BINDING TO D2 RECEPTOR
Protonatable nitrogen that can interact with the anionic
site on the receptor
A phenyl ring to interact with the flat hydrophobic area of
the receptor
The two carbon distance is attained through molecular
bending of the side chain, which contains a three carbon
bridge, toward one of the phenyl rings to approximate a
two carbon distance
Ring geometry is also important in the binding of
phenothiazines to their receptor
11. The most potent position for the electron withdrawing
group is C2 which may help bending the side chain N
through H bond to form dopamine-like conformation
The rank order of potency is position 2>3>4>1
Substitution at C1 has deleterious effect on antipsychotic
activity (which may interfere the bending as in 1) as does
(to a lesser extent) substitution at C4 which may interfere S
binding to receptor
Stronger electron withdrawers are more potent
More than one substitution on the ring system decreases
potency
Oxidizing the ring-sulfur to sulfoxide or sulfone reduces
potency
12. CH3
CH2 CH3
H3C CH3
H CH3 CH2 CH2 CH3 CH3 CH3 CH3 CF3 N CF3
O H O CH3 O C O C O C O S O Cl S O S S O S O O S O CF3
Least potent Most Potent
14. ALKYL SIDE CHAIN
CH3
Increasing or decreasing the
length from 3 carbons N
N CH3
decreases the potency. The
S
further from 3 the less
potent. Two carbon side
Fenethazine
chains increase H1
antagonism (Fenethazine)
Substitutions on the α
carbon decrease potency
CH3
N N
A methyl substituent on the
β carbon can increase or S CH3 CH3
decrease dopamine
antagonism (Trimeprazine) Trimeprazine
15. A methyl substituent on the
β carbon increases H1
antagonism. Substituents CH3
that are larger than methyl N N
decrease antihistaminic S
activity unless they are part
of a heterocycle Methdilazine
(Methdilazine)
Substituents on the γ carbon
decrease dopamine
antagonism but increase N N
anticholinergic activity.
S CH3
These would be expected to
produce less extrapyramidal
CH3
side effects. All the S
piperidines fit this category
Thioridazine
16. Bridging of position 3 of the
side chain to position 1 the
phenothiazine significantly
reduces neuroleptic activity
17. SUBSTITUENTS ON THE γ NITROGEN
There are three classes of phenothiazines based
on the nature of this substituent
1. N,N-Dimethyl (aliphatic)
2. Piperazine
3. Piperidine
18. Thioridazine
S
N S
Piperidine ring
α CH3
Low EPS risk β
Central antimuscarinic
QTc prolongation CH3
N
20. BASIC AMINO GROUP
Maximum neuroleptic potency is observed in
aminoalkylated phenothiazines having a tertiary
amino group.
In general, alkylation of the basic amino group with
groups larger than methyl decreases the
neuroleptic potency.
Quaternization of the terminal nitrogen result in
loss of activity due to inability of these polar
compounds to cross the BBB.
21. POTENCY COMPARISON
Potency at the D2 receptors:
Given equal C2 substituents, ranked from most
potent to least potent - Piperazine > Aliphatic >
Piperidine
Of drugs on the market, however, the rank is -
Piperazine > Piperidine > Aliphatic
Anticholinergic potency: Piperidine > Aliphatic >
Piperazine
22. α Receptor antagonism: Aliphatic > Piperidine >
Piperazine (This may be due to the fact that in
order to get a good antipsychotic effect (D2
antagonism) large doses must be given and so the
α receptor antagonism, although weak, is seen
more)
Extrapyramidal side effects: Piperazine > Aliphatic
> Piperidine (Low anticholinergic potency in the
presence of strong D2 block)
Sedation: Piperidine > Aliphatic > Piperazine
24. METABOLISM
S-oxidation to give sulfoxide derivative inactive.
Terminal N demethylation is still active
C7 hydroxylation inactive compound
Terminal N-oxidation N-oxide derivative is
inactive
28. History/Evolution of Butyrophenone
O
OC2 H5
CH 3 N Meperidine
O O
OC2 H5
N Propophenone
200 x Meperidine as an Analgesic
O
OC2 H5
N Butyrophenone
Analgesia s imilar to Meperidine
O Other activity similar to Chlorpromazine
F OH
N Haloperidol (Haldol)
O Prototype butyrophenone antipsychotic
10x Chlorpromazine
Cl
29. BUTYROPHENONE
R1
O Y
R2
N
X – electron donating group has
highest potency
X
Changing the length of the propyl chain
decreases potency
Replacing the keto oxygen with S, carbon, OH
decreases potency
Y – Replaced with N – Piperazine structure
31. O
F
N NH
N
O
Drope ridol (Inapsine)
Other
Butyrophenone F OH
N
antipsychotics O
CF3
Triflupe ridol
O
F H
N N NH
F
Pimozid e (Orap) "diphenylbu tylpiperidine"
similar to haloperidol, longer duration. Used for Tou rette's Syndrome.
33. Clozapine
7 member central ring
Moderate potency at DA
α1 and α2 adrenergic, 5-HT1A,
5-HT2A, 5-HT2C, M, H1
34. Quetiapine
Lack a substituent on the
aromatic ring
35. Other atypical Resperidone is benzisoxazole and
antipsychotics ziprasidone is the benzisothiazole
containing antipsychotic agents
H3C N
Risperidone is 5-HT2A/D2
F
N
N antagonist with relatively high
O
affinity at histamine H1 and
O N Risperidone adrenergic a1 and a2 receptors. It
Cl H
N has less extrapyramidal side
HCl O
effects
N
N
Ziprasidone is also 5-HT2A/C/D2
S
N Ziprasidone
antagonist with relatively high
affinity at histamine H1 and
adrenergic a1 and a2 receptors. It
can also activate 5-HT1A in brain
and partial D2 agonist activity
37. Aripiprazole
H
O N O
N
N
Cl
Aripiprazole
Cl
It is an arylpiperazine quinoline derivative with complex
pharmacology. Dopamine D2 and serotonin 5-HT1A & 5-
HT2A/C receptor inhibitions are believed to be involved in
its antischizophrenic therapy. It has high affinity partial
agonist effect to some D2 receptors depending on cell
type, which explain its low extrapyramidal side effects.
38. CURRENT CONCEPTS
Presently, antipsychotic agents include many different
chemical structures with a range of activities at different
neurotransmitter receptors (e.g., 5-HT2A antagonism, 5-
HT1A partial agonism).
As a result, structure-function relationships that were relied
upon in the past have become less important.
Instead, receptor-function relationships and functional
assays are more clinically relevant.
Aripiprazole represents a good example of how an
examination of the structure provides little insight into its
mechanism, which is based on dopamine partial agonism.
