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Pharmaceutical chemistry ii (Pc431)

head of Pharmaceutical chemistry
dePartment

Prof. dr . abdel- Ghany ali el- helby

enGy adel hebesh
084741

PC 431 Antipsychotic

Introduction

Schizophrenia is a debilitating disorder of the central nervous system. Its symptoms
have been divided into two classes: positive symptoms, including hallucinations,
delusions and conceptual disorganization; and negative symptoms, including social
withdrawal, blunted affect, and poverty of speech. This disorder reduces the ability of the
individual to interact with the society. The typical neuroleptics used to treat
schizophrenia are highly effective, but are associated with severe extrapyramidal side
effects (EPS).

An antipsychotic is a psychiatric medication mainly used to treat or manage
psychosis (delusions or hallucinations), particularly in schizophrenia and bipolar
disorders. There are two generations of drugs; first generation and second generation. The
first generation is known as typical antipsychotic drugs, the second generation is known
as atypical antipsychotic drugs. Both generations of medication work in a way that block
receptors in the brain’s dopamine pathways, but antipsychotic drugs cover a wide range
of receptor targets. Many side effects have been observed, including lower life
expectancy, weight gain, agranulocytosis, tardive dyskinesia, diabetes, tardice akathisia,
sexual dysfunction, tardive psychosis and tardive dysphrenia.

Antipsychotic drugs are the best treatment now available, but they do not cure
schizophrenia or ensure that there will be no further psychotic episodes, however they are
often very effective in treating certain symptoms of schizophrenia, particularly
hallucinations and delusions. The drugs may not be as helpful with other symptoms, such
as reduced motivation and emotional expressiveness. The older antipsychotics, medicines
like haloperidol (Haldol) or chlorpromazine (Thorazine), may even produce side effects
that resemble the more difficult-to-treat symptoms. Lowering the dose or switching to a
different medicine may reduce these side effects; the newer medicines, including

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olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and aripiprazole
(Abilify) appear less likely to cause this problem. Sometimes when people with
schizophrenia become depressed, other symptoms can appear to worsen. The symptoms
may improve with the addition of an antidepressant medication.

Patients and families sometimes become worried about the antipsychotic medications
used to treat schizophrenia. In addition to concern about side effects, they may worry that
such drugs could lead to addiction. However, antipsychotic medications do not produce a
"high" or addictive behavior in people who take them.

Another misconception about antipsychotic drugs is that they act as a kind of
mind control, or a "chemical straitjacket." Antipsychotic drugs used at the appropriate
dosage do not knock out people or take away their free will. While these medications can
be sedating, these drugs are not used because of the sedation but because of their ability
to diminish the hallucinations, agitation, confusion, and delusions of a psychotic episode.
Antipsychotic medications should eventually help an individual with schizophrenia to
deal with the world more rationally.

In the next few pages, 3 antipsychotic drugs will be observed along with their
mode of action, structural activity relationship and their synthesis, along with recent
information of antipsychotic drugs.

Clozapine (Lepronex)

Clozapine is an antipsychotic medication used in the treatment of schizophrenia.
It is in the class of benzodiazepine. It is the first atypical antipsychotic to be developed,
however it was withdrawn by the manufacturer in 1975 due to its side effect which is
agranulocytosis, which is a condition involving a dangerous decrease in the number of
white blood cells, that led to death in some patients.

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8-chloro-11-(4-methylpiperazin-1-yl)-
5H-dibenzo[b,e][1,4]diazepine

Mode of action

Clozapine is classified as an atypical antipsychotic drugs because it binds to
serotonergic as well as dopamine receptors. In particular, clozapine interferes to a lower
extent with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high
affinity for the D4 receptor, but it does not induce catalepsy (seizure with loss of
consciousness). This proves that clozapine is preferentially more active at limbic than at
striatal dopamine receptors and may explain why clozapine does not have extrapyramidal
side-effects together with strong anticholinergic activity.

Several metabolites of Clozapine show binding similar to Clozapine. N-
desmethylclozapine may contribute significantly to the atypical effects of Clozapine
treatment. N-desmethylclozapine acts a an agonist and/or partial agonist at D2, D3, δ-
opioid, M1, M2, M3, M4, M5 receptors, and an antagonist/inverse agonist at 5-HT2A
and 5-HT2C receptors.

Clozapine is also a partial agonist at the 5-HT1A receptor, improving depression, anxiety,
and the negative cognitive symptoms. Clozapine also is a strong antagonist at different
subtypes of adrenergic, cholinergic and histaminergic receptors, the last two being
predominantly responsible for its side-effects.

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Synthesis

Clozapine is usually used as a last resort in patients that have not responded to
other anti-psychotic treatments due to its danger of causing agranulocytosis as well as the
costs of having to have blood tests continually during treatment. It is, however, one of the
very effective anti-psychotic treatment choices. Patients are monitored weekly for the
first six months. If there are no low counts the patient can be monitored every two weeks
for an additional six months. Afterwards, the patient may qualify for every 4 week
monitoring.

Contraindications

Clozapine is contraindicated in individuals with uncontrolled epilepsy, myeloproliferative
disease, or agranulosis with prior clozapine treatment.

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Olanzapine (Zyprexa)

The FDA approved Olanzapine, an antipsychotic drug manufactured by the Eli, Lily and
company, in October 1996, for the treatment of psychotic disorders. Olanzapine is a
yellow crystalline solid and practically insoluble in water. It is a thieno-benzodiazepine
analog with the chemical name and structure given below.

2-methyl-4-(4-methyl-1- piperazinyl)-10 thieno [2,3-b][1,5] benzodiazepine.

Behavioral pharmacological in vivo studies show that olanzapine is an antagonist of
dopamine, serotonin, and acetylcholine which is the same receptors as that of clozapine.

Mode of Action

The exact mechanism of action of olanzapine is not known. It may work by
blocking receptors for several neurotransmitters (chemicals that nerves use to
communicate with each other) in the brain. It binds to alpha-1, dopamine, histamine H-1,
muscarinic, and serotonin type 2 (5-HT2) receptors.

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Synthesis

Structure activity relationship of Clozapine and Olanzapine
The modification of Ri in phenyl ring was exclusively done in the present study,
since this position was most accessible to be substituted in the first step of synthesis. As
seen in a series of the compounds with hydrogen or methyl group in R, of s-triazol ring,
introduction of such electron-withdrawing substituents as chlor, nitro or trilluoromethyl
group in Ri produced a pronounced enhancement of the over-all biological activity.
However, the enhancing effect was not necessarily parallel to the electron-withdrawing
power of substituent, and the compounds with chlor group appeared to be most potent in
most of tests. On the other hand, the effect of such electron-releasing substituent as
methyl or methoxy group in R, was not so remarkable as that of electron-withdrawing
groups, but was effective to some extent in enhancing the muscle relaxant and calming
activities.
Whatever substituent was introduced in R,, substitution with methyl group in R, of s-
triazolo ring was always effective in enhancing all parameters of the biological activities.
Exploration of the effects of substitution with various kinds of groups in R, was made on
the compound 7 with chlor group in R, of phenyl ring. The over-all biological activity
was attained to maximum by replacement with methyl group and was decreased slightly

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by ethyl group. Substitution of alkyl group with long chain such as n-hexyl group, or of
bulky phenyl or benzyl group in R 2 lowered the biological activity remarkably.

The effects of substituent in R3 of phenyl ring of 6 position were studied only in the case
of methoxy group. The presence of methoxy group in R3 resulted in almost complete loss
of activity.

Haloperidol

Haloperidol is the most widely used typical antipsychotic, it is in the butyrophenone class
of antipsychotic medications. It is an older antipsychotics used in the treatment of
positive and negative schizophrenia and in acute psychotic states and delirium.
Long-term use of the drug, however, results in an irreversible motor disorder involving
the orafacial muscles and the extremities, which has been a source of major concern, in
the medical community

4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one
Structure activity relationship
Structure requirement for antipsychotic activity are as follow
1) The attachment of a tertiary amino group, the 4th carbon is essential
2) The basic nitrogen is usually incorporated into a 6 member ring ( usually 4-
substitued).
3) Optimal activity is seen when Ar is aromatic
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4) Y can very and assists activity ex. OH of haloperidol
5) 4-flourine substitution of the benzene ring = most potent
6) Keto group is essential; reduction, thioketone, phenoxy = decrease activity
7) Chance of the propyl chain decrease activity.

Mode of action

Haloperidol, is a tertiary amine that tends to form interphase between water/air or
water/lipid at very low concentrations of the order of 10-7 M. It has been shown that
neuroleptic drugs tend to decrease the permeability of a variety of biological membranes
for various inorganic and organic molecules, including water, and that they exert this
effect in minute concentrations. That is to say that these drugs act like potent membrane
permeability blockers. Haloperidol is a dopamine antagonist. Its major site of action is
the dopamine D2 receptors, which has high affinity for the drug. The average dose of
Haloperidol is about 20 mg/day per person.

Synthesis

Haloperidol has been clinically tested and in the market by 1960. Haloperidol has been
used clinically in psychiatry, obstetrics, and anesthesiology, and its pharmacology has

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been extensively reported

Chlorpromazine

Chlorpromazine is one of the oldest typical antipsychotic, Its use has been described as
the single biggest advance in psychiatric treatment, dramatically improving the prognosis
of patients in psychiatric hospitals worldwide. It was the prototype for the phenothiazine
class, which later grew to comprise several other agents.

Mode of action
Chlorpromazine works on a variety of receptors in the CNS, producing anticholinergic,
antidopaminergic, antihistaminic and antiadrenergic effects. Its anticholinergic properties
causes constipation, sedation and hypotension and relieves nausea. It also has anxiolytic
properties. Its antidopaminergic properties cause EPS. Chlorpromazine inhibits clathrin-
mediated endcytosis. Chlorpromazine is known to cause tardive dyskinesia (involuntary
repetitive body movements), which can be irreversible. It is often administered in acute
settings as a syrup, which has a faster onset of action than tablets. Subcutaneous injection
is not advised, and administration is limited to severe hiccups, surgery, and tetanus.

3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-1-amine

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Structure activity relationship
 Essential for activity
1) Linear Tricyclic ring system
2) Electron withdrawing group ex. X (with unshared electron) at pos. 2 to form H-
bond with N10 side chain nitrogen, to develop dopamine like arrangement
3) Sulphur at pos. 5 is considered as a receptor binding function.
4) 3 carbon side chain between N10 and N of the amino side chain.
If 2 carbons  antihistamic
If 4 carbons  antitussive

 Decrease activity
1) Substitution at pos. 1  prevents H-bond with protonated N
2) Substituion at pos. 4  prevents binding with DA-OH
3) Branching at the beta-carbon of the side chain; levo is more active then
dextro
4) If a pheny or bulky group  restricts the free rotation of the side chain=
decreases potency
5) Quaternization of the side chain nitrogen decrease lipid solubility=
decrease activity
6) Substitution at any other position of the phenothiazide ring

 Optimum & increase activity by
1) Dimethylamino group of N10 chain is optimal for activity (CPZ=1)
2) Monoethyl decrease activity as well as N’N diethyl amino
3) Terminal dimethylamino into a cyclic structure decrease activity

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Synthesis

Other antipsychotic drugs include;

Aripiprazole (abilify)
• Usual dose is 15-30 mg/day
• Low incidence of motor side effects (extrapyramidal symptoms)
• Less likely to cause weight gain than other atypical antipschotics
May contribute to diabetes and elevated blood sugar

Risperidone (Risperdal)
• Less sedative than other atypical antipsychotics
• Available in a long-acting formulation
• More likely than other atypical psychotics to cause motor side effects (extrapyramidal
symptoms)
Risk of weight gain and diabetes, but less than clozapine or olanzapine

Quetiapine (Seroquel)
Risk of weight gain and diabetes, but less than clozapine or olanzapine

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Ziprasidone (Geodon)
• Usual dose is 80-160 mg/day; intramuscular formulation available
• Less likely to cause weight gain than other atypical antipsychotics
May contribute to cardiac arrhythmia, and must not be combined with other drugs having
this effect

The development of new antipsychotics, and the relative efficacy of different
ones, is an important ongoing field of research. The most appropriate drug for an
individual patient requires careful consideration.

References

 Antipsychotic drugs,

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http://mentalhealth.about.com/cs/psychopharmacology/a/antipsy.htm, verified on
April 19th 2010

 Chlorpromazine, http://en.wikipedia.org/wiki/Chlorpromazine, verified on April
20th 2010

 Clozapine, http://en.wikipedia.org/wiki/Clozapine, verified on April 19th 2010

 Haloperidol, http://en.wikipedia.org/wiki/Haloperidol, verified on April 19th 2010

 Olanzapine, http://en.wikipedia.org/wiki/Olanzapine, verified on April 19th 2010

 Olanzapine, http://www.medicinenet.com/olanzapine/article.htm verified on April
19th 2010

 Wikipidia, http://en.wikipedia.org/wiki/Antipsychotic, verified on April 19th 2010

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