Transcript fff-Antipsychotics (Neuroleptics)

Antipsychotics
(Major tranquilizers or Neuroleptics)
These drugs are useful in the treatment of psychoses
especially schizophrenia, counteract or minimize
hallucination and delusion
Advantages
not affect consciousness or depress vital centers
(contrary to the sedatives and hypnotics).
not induce psychological or physical dependence
over dosage is not fatal to adults.
have antiemetic and sympatholytic action.
Mechanism of action
It involves antagonism of brain dopamine receptors
especially D2-type.
For atypical agents such as dibenzodiazepine
(clozapine) and benzisoxazoles that have less EPS,
they interact with dopamine D2-receptors and other
receptors e.g acetylcholine, histamine and serotonin
Side effects of neuroleptics
They can be attributed to their antagonistic activity to
a variety of CNS receptors which include:
1- Blockade of adrenergic (a1/ a2) and histamine (H1)
receptors: hypotension and sedation
2- Antagonism of muscarinic acetylcholine receptors
(M1) : They cause anticholinergic actions on cardiac,
ophthalmic, GIT, bladder, and genital tissue.
3- Antagonism of D2 receptors in nigrostriatal
pathway: EPS.
4- Antagonism of D2-receptors in chemorecep
tor trigger zone in the brain stem is responsible
for their antiemetic effects e.g. promazine
5- Metabolic and endocrine side effects: weight
gain, hyperprolactinemia and gynecomastia.
6- Potentiate the action of CNS depressants.
7- Other adverse reactions are jaundice,
agranulocytosis and convulsions.
N.B. The anticholinergic action of atypical clozapine may be
beneficial in negative symptoms of schizophrenia.
Structural requirements for all neuroleptic drugs
1. A straight chain of three carbon atoms linking the
basic ring nitrogen with a carbon, nitrogen, or oxygen
atom.This atom may be a part of benzoyl
group,phenothiazine or thioxanthene (tricyclic system).
Y = C, N, O
N
CH2 CH2 CH2 Y
2. A six-membered basic heterocyclic ring, such as
piperazine or piperidine substituted in positions 1
and 4; the best substituents in position 4 are phenyl,
anilino, methyl, or hydroxyethyl moieties.
Thus, all neuroleptics act at the molecular level via blockade of
D2 receptors because they have these two features.
In complexation with dopamine receptors, "S-shaped"
conformation of the four-atom sequence that links an aromatic
ring to 3ry basic nitrogen in most neuroleptics may be involved.
d
Cl
d
F
N
N
R
d
NH2
S
HO
HO
F
(a)
(b)
(c)
The “S-shaped” conformation of piperidylidene thioxanthene
(a) and diphenylbutylamines (b), has the same distance d as
dopamine (c) molecule in its extended conformation.
Classification of antipsychotics
I- Phenothiazine and thioxanthene derivatives.
II- Butyrophenone and diphenylbutyl piperidine derivatives
III - Benzamide derivatives
IV- Benzazepine derivatives
V- Indole derivatives.
VI- Benzisoxazoles.
VII- Antimanic agents.
I- Phenothiazine and thioxanthene derivatives
5
4
6
A) Phenothiazine derivatives
S
7
3
They are characterized by a
8
10
2 R-2
N
9
1
lipophilic fused tricyclic system
lipophilic portion
N
linked via the nitrogen atom of the
intermediat chain
hy drophilic portion
central ring through intermediate
chain to a hydrophilic 3ry basic amine.
Interaction of phenothiazines and thioxanthenes with
R-2
dopaminergic receptors
Phenothiazines interact with the
HC
N
dopamine receptor at three
H
R
N
S
sites A, B, and C to produce a

N


response. The order of structural
Site A
Site B
Site C
specificity at these
Proposed conformation in contact
sites is B > C > A.
with the neuroleptic receptors
3
Site B (the intermediate chain)
1.
S
Alkyl chain should contain 3 carbon atoms
N
(n-propyl chain) which are optimal for activity.
X
N
2. If two carbons, it gives phenothiazines
X
with either anticholinergic (ethopropazine)
X = Me promethazine
or antihistaminic (promethazine) activities X = Et Ethopropazine
without antipsychotic due to their isopropyl (Antiparkinsonian drug)
intermediate chain can not assume the preferred conformation.
3.
The R group located on the ß-carbon is important for
structural specificity (certain degree of free rotation is
necessary) due to it causes steric effects.
a) If R = H , good neuroleptic potency is exhibited.
b) If R = CH3, it enhances antihistaminic effects and
decreases neuroleptic activity.
c) If R = bulky group (phenyl or part of a ring), it decreases
neuroleptic potency
Site A (hydrophilic 3ry basic amine)
1- Site A is responsible for structural specificity due to
molecule must enter into narrow slot. Thus, if two
hydrogen atoms attached to the nitrogen are replaced:
a) By methyl groups does not reduce the activity.
b) By bulky alkyls decreaes activity (increased steric effect).
2- Replacement of the terminal dimethylamino group by
piperazine or N-methylpiperazine group increases activity.
3- Quaternary N atom at the side chain decrease lipid solubility
and penetration into CNS and loss of activity.
Site C (lipophilic phenothiazine nucleus):
1- The two flat aromatic rings are at right
angles due to folding of phenothiazine
nucleus. So, the R-2 substituent
is too far from the receptor and
not exerts any steric influence.
S
N
R-2
R-10
2- Substitution of ring H at 2-position only leads to increase
activity; otherwise decreases potency.
3- The presence of an electron attracting but not ionizable gp at 2position increase potency e.g. Cl (chloropromazine) and CF3
(trifluoropromazine).
4- Derivatives with 2-thioalkyl retain activity while the 2-OH
derivatives are weakly active.
5- In the preferred conformation of
chlorpromazine, its side chain tilts
toward the 2-chlorine-substituted ring
due to attraction of the amine side-chain
(protonated at physiologic pH) toward
the ring containing the chlorine atom.
a) propylamines
S
N
The electronegative chlorine atom is
responsible for imparting asymmetry to
chlorpromazine.
CH 3
N
CH 3
Promazine (Sparine)
Phenothiazines and related compounds
lacking a chlorine at 2-position are
inactive as neuroleptic.
S
N
Cl
N
CH3
CH3
Classification of Phenothiazines
They are classified according to the
hydrocarbon side chain into:
a) propylamines
b) piperidines
c) piperazines
Chloropromazine
2-Chloro-10-[3-(dimethylamino)propyl]phenothiazin
e hydrochloride
a) Propylamines
Chlorpromazine HCI (Largactil).
It is the prototype and used in the treatment of schizophrenia,
control of acute psychosis and acute mania.
It is also used as antiemetic in postoperative nausea and
vomiting.
Assay: non-aqueous titration with 0.1 M perchloric acid.
Synthesis:
S
N
Cl
S
Heat
N
H
H
b) Piperidines
Thioridazine HCl (Melleril).
It has a relatively low EPS, low
antiemetic activity but higher
anticholinergic effect.
Cl
CN
S
S
Reduction
N
Cl
NH2
(CH3)2SO4
S
N
Cl
N
CH3
CH3
N
Cl
CN
S
It is 10-[2-(1-Methyl-2-piperidyl)-ethyl]
2-(methylthio)phenothiazine
N
SCH3
c) Piperazine
Trifluoperazine HCl (Stelazine).
 It is 2-trifluoromethy-10-[3-(4methy-1-piperazinyl)propyl]phenothiazine
 It is potent antipsychotic, with
high EPS and low sedation and
hypotensive effects.
Fluphenazine decanoate (long acting)
 The duration of action of
fluphenazine with a free OH moiety
can be prolonged by preparation
of long chain fatty acid esters.
 A single I.M. every 2-3 weeks
with ester to avoid drug regimen
and mal-absorption.
CH3
N
Thioridazine HCl
S
N
CF3
N
N
CH 3
Trifluoperazine HCl
S
N
CF3
N
N
OH
B) Thioxanthene derivatives (Modified phenothiazines)
Isosteric replacement of N atom of phenothiazine with sp2
carbon (methylidene) led to thioxanthenes.
Thioxanthenes are also nonpolar in which substituent at 2position led to formation of either cis (Z) or trans (E) isomers.
Z isomer is more active than trans isomer or its saturated
analog because it is superimposable on dopamine receptors.
Their pharmacological action and adverse effects are very
similar to phenothiazine derivatives.
10
5
4
Chlorprothixene (Taractan)
S
6
3
7
9
2
Cl
It is the biological isostere of chlorpromazine.
CH
N
It is used in the treatment of schizophrenia.
CH
It also has antihistaminic, antiemetic and
hypotensive properties.
Z-2-Chloro-9-(3-dimethyl
8
1
3
3
aminopropylidine)
thioxanthene
Metabolism of phenothiazine and thioxanthenes
The 7-hydroxylated phenothiazines as well as, the mono- and
di-desmethylated products are active in vivo at dopamine D2
receptors, whereas the sulfoxide is inactive.
Most of the thioxanthenes do not form ring-hydroxylated
derivatives.
Thus, it can be concluded that in all tricyclic compounds, the
structural features associated with high antipsychotic potency are:
1. A tricyclic ring with a six- or seven-membered central ring.
2. A side chain of 3 atoms between central ring and terminal NH2
group.
3. An electron-attracting group, such as chloro or trifluoromethyl,
at 2- position of tricyclic ring.
II- Butyrophenone and diphenylbutyl piperidine
derivatives
a) Butyrophenone derivatives
In 1950, Janssen prepared propiophenone and
butyrophenone analogs of meperidine in trial to
increase the analgesic potency of meperidine.
The propiophenone analog had 200 times analgesic
potency of meperidine but the butyrophenone analog
displays activity resembling that of chlorpromazine but
they are less toxic.
O
COOC2H5
H3C
N
Meperidine
COOC2H5
COOC2H5
N
Propiophenone analog
N
O
Butyrophenone analog
Structure-activity Relationships
All butyrophenones have the following general structure:
X
N
R
X = F or OCH3
O
1) The potent compounds have p-fluorophenyl and the distance
between its center and the 3ry nitrogen in the preferred
conformation of haloperidol is 7.3 Å.
2) The attachment of 3ry amino group to the 4th carbon of the
butyrophenone skeleton is essential for activity.
3) Lengthening, shortening, or branching decreases activity.
4) Replacement of keto moiety with thioketone or reduction of
C=O group decreases neuroleptic potency.
5) the 3ry basic nitrogen is usually incorporated into sixmembered ring (piperidine or piperazine) that is substituted in
the para-position.
OH
Haloperidol (Haldol)
O
It binds with high affinity to
N
Cl
dopamine D2 and serotonin F
5-HT2,receptors in brain.
4-[4-(p-Chlorophenyl)-4-hydroxy)
It is used in the treatment of piperidino]-4-fluorobutyrophenone
schizophrenia and acute psychosis.
It causes a high incidence of extrapyramidal reactions.
Assay: non-aqueous titration with 0.05M perchloric acid.
Haloperidol decanoate is long-acting inj. (4-6 weeks).
H
Droperidol
O
N
1-{l-[3-(p-Fluorobenzoyl)propyl]1,2,3,6-tetrahydro-4-pyridyl}2-benzimidazolinone.
N
O
N
F
It is a short-acting and used in anesthesia for its
sedating and antiemetic effects in combination
(Innovar) with fentanyl (narcotic analgesic).
b) Diphenylbutyl piperidine neuroleptics
Modification or partial duplications of haloperidol by introducing
4-fluorophenyl moiety led to long acting derivatives such as
pimozide and penfluridol (due to their
O
F
high hydrophobic characters).
N
N
NH
They are taken orally once a week
in chronic schizophrenia.
F
III- Benzamide derivatives
pimozide
The o-methoxyprocainamide is a compound with local
anesthetic properties and potent antiemetic action.
Further modification of the molecule yielded metoclopramide.
1- Metoclopramide (Primperan, Plasil)
It possesses antiemetic activity (modifies gastric
motility).
It was found to antagonize dopamine D2- receptors in
the chemoreceptor trigger zone of the brain stem.
2- Pyrrolidinyl-containing benzamides
a) Sulpiride (Dogmatil)
Sulpiride has little sedative effect and lack EPS which
is due to preferential effect on limbic in comparison
with striatal tissue (extrapyramidal).
Its hydrophilic properties causes its poor oral
absorption, limited penetration into CNS and resulting
low potency.
b) Remoxipride
It is orally well absorbed and has nearly the same
potency as haloperidol but with fewer incidences of
extrapyramidal and autonomic side effects.
It causes aplastic anemia, that may limit its use as
antipsychotic drug.
CH3O
CH3O
O
N
H
H2N
N
C2H5
N
O
H
C2H5
H
C2H5
H2NO2S
Cl
Metoclopramide
S-(-)-Sulpiride
CH3O
N
O
N
H
OCH3
H
N
C2H5
Br
S-(-)-Remoxipride
CH3
IV- Benzazepine Derivatives.
1) Clozapine (Clozaril)
R
N
N
N
N
N
N
Cl
It is dibenzazepine antipsychotic
with minimal EPS and alleviates
negative symptoms of
schizophrenia.
Cl
N
H
O
Loxpine
Amoxapine
(R=CH3)
( R=H)
Its serious drawback is the fatal agranulocytosis.
It has low affinity for dopamine D1 and D2 receptors in
comparison to its affinity at adrenergic a1; and a2, H1,
muscarinic M1 and serotonin 5-HT2A, receptors, thus, its
special use may be through interactions with other receptors.
2) Loxapine (Loxitane)
2-Chloro-11-(4-methyl-1-piperazinyl)dibenz[b,f][l,4]oxazepine.
It is typical neuroleptic with mainly antidopaminergic activity
at D2- receptors.
3) Amoxapine(Asendin)
Loxapine undergoes N-demethylation to form
amoxapine which is used clinically as antidepressant
It binds to D2 receptors and inhibits the norepinephrine
neurotransporter to block norepinephrine re-uptake, a
correlate of antidepressant activity.
V- Indole derivatives and isosteres
Their antipsychotic activity is based on that serotonin
(5-hydroxytryptamine) is involved in schizophrenia;
therefore certain indolamine analogs might be useful
neuroleptic agents
The chemical structure of some neuroleptic (droperidol
and pimozide) are indole or its isostere
Molindone (Moban):
3-Ethyl-6,7-dihydro-2-methyl-5(morpholinomethyl)indole-4(5H)oneO
O
CH2CH3
. HCl
N
CH3
N
H
It is a tetrahydroindolone derivative which used in
acute and chronic schizophrenia.
It is less potent than haloperidol in blocking D2
receptors, however, it can produce EPS.
It is rapidly absorbed and metabolized when given
orally ( last more than 24 hours.)
Sertindole (Serdolect).
It is indole and acts as serotonin
5-HT2 receptor antagonist with no
affinity for dopaminergic D2 receptors.
F
N
Cl
N
NH
N
O
Advantages:
1. It is as effective as haloperidol in treatment of acute
and chronic schizophrenia,
2. much lower incidence of EPS.
3. It is non-sedating and long lasting (several days).
VI- Benzisoxazoles
The proposal that combination D2/5-HT2 antagonists
may produce atypical antipsychotic effects.
N O
Risperidone
O
It is 5-HT2/D2 antagonist.
F
3-(4-piperidinyl)-1,2-benzisoxazole
N
N
N
CH3
The anti-serotonergic effects of risperidone are
proposed to un-inhibit dopaminergic
neurotransmission in the striatum and cortex,
reducing the severity of D2 antagonist-induced EPS
and alleviating negative symptoms of schizophrenia,
while maintaining a blockade of limbic system D2
receptors. It is well absorbed orally.
VII- Antimanic agents
Lithium salts are used as antimanic agents.
Lithium chloride is not used because it is hygroscopic
and more irritant than carbonate or citrate salts to the
GIT.