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College of Pharmacy 4th stage /Lecture 4 Medicinal Chemistry Dr.Narmin Hussen

Antipsychotic drugs

Schizophrenia

The psychoses affect approximately 1% of the population in all cultures. They are

psychogenic mental disorders involving a loss of contact with reality. The psychotic

disorders include schizophrenia and the manic phase of bipolar (manic–depressive)

illness.

The most common is schizophrenia, in which perception, thinking, communication,

social functioning, and attention are altered.

Schizophrenia is defective dopamine neurotransmission relative excess of central

dopaminergic activity.

Symptoms are called positive (e.g., delusions, hallucinations) or negative (e.g., flat

affect, speech poverty); and cognitive dysfunction (disorganization) may occur.

Some researchers have suggested that dopamine systems in the mesolimbic pathway may

contribute to the 'positive symptoms' of schizophrenia (whereas problems with dopamine

function in the mesocortical pathway may be responsible for the 'negative symptoms'.

The etiology of psychosis remains unknown, although genetic, neurodevelopmental and

environmental causative factors have all been proposed.

Typical antipsychotics (e.g., chlorpromazine, haloperidol) are better for treating positive

signs than negative signs. For treating negative signs, the newer (atypical) antipsychotic

drugs (e.g., clozapine, risperidone) target D2 receptor and other receptors.

The bases of the atypical group’s activity against negative symptoms may be serotonin-

2A receptor (5- HT2A) block, block at receptors yet to be determined, and possibly

decreased striatal D2 block.

The conventional typical antipsychotics (neuroleptics) are characterized by the

production of EPS, roughly approximating the symptoms of Parkinson disease. Atypical

antipsychotics date from the discovery of clozapine, its antipsychotic properties, and its

much lower production of EPS. It has reduced EPS, has increased activity against

negative symptoms, and, in addition to its DA-blocking ability, is a 5-HT2A antagonist

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Phenothiazines SAR of phenothiazine antipsychotic agents:

Phenothiazines have a tricyclic structure (6-6-6 system) in which two benzene rings are

linked by sulfur and a nitrogen atom. The best position for substitution is the 2-position.

Activity increases (with some exceptions) as electron-withdrawing ability of the 2-

substituent increases (e.g., chlorpromazine vs. promazine).

The three-carbon chain between position 10 and the aliphatic amino nitrogen is critical

for neuroleptic activity. Shortening or lengthening the chain at this position 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.

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.

As expected, branching with large groups (e.g., phenyl) decreases activity, as does

branching with polar groups. Methyl branching on the β-position has a variable effect on

activity.

Decreases in size from a dimethylamino group (e.g., going to a monomethylamino)

greatly decrease activity, as do effective size increases, such as the one that occurs with

N, N-diethylamino group.

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The sulfur atom at position 5 is in a position analogous to the p-hydroxyl group of DA,

and it was also assigned a receptor-binding function.

Several piperazine phenothiazines are esterified at a free hydroxyl with long-chain fatty

acids to produce highly lipophilic and long-acting prodrugs.

Because of the high lipophilicity of most antipsychotic drugs, they are highly membrane

and protein bound (92%–99%) mostly to albumin. They accumulate in the brain, lung,

and other tissues with a rich blood supply and also enter the fetal circulation and breast

milk.

Pharmacokinetic of Phenothiazine:

Most phenothiazines undergo significant first-pass metabolism. Chlorpromazine and

other phenothiazines are metabolized extensively by CYP2D6.

A major route is 7-hydroxylation of the tricyclic system. Because electron-withdrawing

2-Cl substituent blocks the hydroxylation on chlorophenyl ring, the hydroxylation occurs

at 7-position rather than 2-position. Thus, the major initial metabolite is frequently the 7-

hydroxy compound (active metabolite). This compound is further metabolized by

conjugation with glucuronic acid.

Phenothiazine derivatives:

Chlorpromazine Hydrochloride: Chlorpromazine was the first phenothiazine compound introduced into therapy. It is still

useful as an antipsychotic. Other uses are in nausea, vomiting, and hiccough.

Oral doses of chlorpromazine and thioridazine have systemic availability of 25% to 35%

because of significant first-pass metabolism. Chlorpromazine and other phenothiazines

are metabolized extensively by CYP2D6. In contrast, bioavailability of chlorpromazine

may be increased up to 10-fold with injections, but the clinical dose usually is decreased

by only threefold to fourfold.

Chlorpromazine may weakly induce its own hepatic metabolism, because its

concentration in blood is lower after several weeks of treatment at the same dosage. Alterations of GI motility also may contribute.

The drug has significant sedative and hypotensive properties, possibly reflecting central

histaminergic and peripheral α1-noradrenergic blocking activity, respectively.

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Promazine HCl. Promazine (Sparine), was introduced into antipsychotic therapy after its 2-chloro-

substituted relative.

The 2H-substituent vis-à-vis the 2Cl substituent gives a milligram potency

decrease as an antipsychotic.Tendency to EPS is also lessened, which may be

significant, especially if it is decreased less than antipsychotic potency.

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Triflupromazine Hydrochloride.

It has greater milligram potency as an antipsychotic, higher EPS, but lower sedative and

hypotensive effects than chlorpromazine. The 2-CF3 versus the 2-Cl is associated with

these changes. Overall, the drug has uses analogous to those of chlorpromazine.

Thioridazine Hydrochloride: The drug has high anticholinergic activity, and this activity in the striatum,

counterbalancing a striatal DA block, may be responsible for the low EPS.

The drug has sedative and hypotensive activity in common with chlorpromazine and

less antiemetic activity. At high doses, pigmentary retinopathy has been observed.

Its major metabolites include N-demethylated, ring hydroxylated, and S-oxidized

products.Thioridazine is prominently converted to the active metabolite mesoridazine

which probably contributes to the antipsychotic activity of thioridazine.

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Prochlorperazine Maleate (Compazine):

Prochlorperazine maleate is in the piperazine sub group of the phenothiazines,

characterized by high-milligram antipsychotic potency, a high prevalence of EPS, and

low sedative and autonomic effects.

Prochlorperazine is more potent on a milligram basis than its alkylamino counterpart,

chlorpromazine. Because of the high prevalence of EPS.

Fluphenazine Hydrochloride.

The member of the piperazine subgroup with a trifluoromethyl group at the 2-position of

the phenothiazine system and the most potent antipsychotic phenothiazine on a milligram

basis is fluphenazine hydrochloride

It is also available as two lipid-soluble esters for depot intramuscular injection, the

enanthate (heptanoic acid ester) and the decanoate ester. These long-acting preparations

have use in treating psychotic patients who do not take their medication or are subject to

frequent relapse.

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Thiothixene:

The thioxanthene system differs from the phenothiazine system by replacement of the N-

H moiety with a carbon atom doubly bonded to the propylidene side chain. With the

substituent in the 2-position, Z-and E-isomers are produced.

In accordance with the conceptthat the presently useful antipsychotics can be

superimposed on DA, the Z-isomers are the more active antipsychotic isomers.

The compounds of the group are very similar in pharmacological properties to the

corresponding phenothiazines. Thus, thiothixene displays properties similar to those of

the piperazine subgroup of the phenothiazines.

Ring Analogs of Phenothiazines:

Benzazepines, Dibenzoxazepines, and Dibenzodiazepines:

Additional tricyclic antipsychotic agents are the benzazepines, containing a seven-

membered central ring (6-7-6 system).

These newer atypical antipsychotics include dibenzodiazepines (clozapine with 2-Cl),

dibenzoxazepines (loxapine with 2-Cl), thienobenzodiazepines (olanzapine without 2-

substituent), and dibenzothiazepines (quetiapine without 2-substituent) .

Loxapine (Daxolin):

Loxapine, an effective antipsychotic, blocks D2-type receptors and has side effects

similar to those reported for the phenothiazines.

Its metabolism involves aromatic hydroxylation to give several phenolic metabolites that

have higher affinity for D2 receptors than the parent. It is also N-demethylated to yield

amoxapine (an antidepressant drug), which inhibits norepinephrine (NE) neurotransporter

to block neuronal NE reuptake.

The structural relationship to the phenothiazine antipsychotics is apparent. Examples in

this group are clothiapine, metiapine, zotepine, and others. They have electron-

withdrawing groups at position 2, relatively close to the side-chain nitrogen atoms.

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Clozapine (Clozaril):

It is effective against both positive and negative symptoms of schizophrenia and has a

low tendency to produce EPS. However, there are legal restrictions on its use because

of a relatively high frequency of agranulocytosis.

Clozapine is metabolized preferentially by CYP3A4 into demethylated,

hydroxylated, and N-oxide derivatives that are excreted in urine and feces.

Olanzapine and Quetiapine:

Clozapine analogs, olanzapine (Zyprexa) and quetiapine (Seroquel) possess tricyclic

systems with greater electron density than chlorpromazine.

The drugs are atypical antipsychotics. Olanzapine is a more potent antagonist at D2 and

5-HT2A receptors than clozapine and is well absorbed, but about 40% of an oral dose is

metabolized before reaching the systemic circulation. Major readily excreted metabolites

of olanzapine are the inactive 10-N-glucuronide and 4-nor derivatives, formed mainly by

the action of CYP1A2, with CYP2D6 as a minor alternative pathway. It may have even

lower risk than risperidone and has achieved widespread use.

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Overall, these two compounds should bind less strongly to D2 receptors and permit more

receptor selectivity among receptor subtypes than typical antipsychotics.

Quetiapine is highly metabolized by hepatic CYP3A4 to inactive and readily excreted

sulfoxide and acidic derivatives.

Fluorobutyrophenones:

The fluorobutyrophenones belong to a much-studied group of compounds, many of

which possess high antipsychotic activity.

Attachment of a tertiary amino group to the fourth carbon of the butyrophenone skeleton

is essential for neuroleptic activity; lengthening, shortening, or branching of the three

carbon propyl chain decreases neuroleptic potency.

This aliphatic amino nitrogen is required, and highest activity is seen when it is

incorporated into a cyclic form. A p-fluoro substituent aids activity. The C=O group

gives optimal activity, although other groups, C(H)OH and C(H)aryl, also give good

activity.The long N-alkyl substituent could help promote receptor affinity and produce

receptor antagonism activity and/or inverse agonism.

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Haloperidol, (Haldol):

Haloperidol is a potent antipsychotic useful in schizophrenia and in psychoses associated

with brain damage.

It can also help prevent suicide in people who are likely to harm themselves. It also

reduces aggression and the desire to hurt others. It can decrease negative thoughts and

hallucinations.

Haloperidol-induced dyskinesias may involve neurotoxicological metabolite similar to

dopaminergic toxicant MPP+.

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Risperidone (Risperdal, a benzisoxazole):

Risperidone has the structural features of a hybrid molecule between a butyrophenone

antipsychotic and a trazodone-like antidepressant. It is an important atypical

antipsychotic.

Risperidone is metabolized in the liver by CYP2D6 to an active metabolite, 9-

hydroxyrisperidone. Because this metabolite and risperidone are nearly equipotent, the

clinical efficacy of the drug reflects both compounds , risperidone appears to be most

likely to produce EPS.

Ziprasidone:

Ziprasidone (Geodon, a benzisothiazolpiprazinylindolone derivative) also has the

structural features of a hybrid molecule between a butyrophenone antipsychotic and a

trazodone-like antidepressant.

It is highly metabolized to four major metabolites, only one of which, S-

methyldihydroziprasidone, likely contributes to its clinical activity. In humans, less than

5% of the dose is excreted unchanged. Reduction by aldehyde oxidase accounts for about

66% of ziprasidone metabolism; two oxidative pathways involving hepatic CYP3A4

account for the remainder.

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Β-Aminoketones: In addition to the β-aminoketone group, there must be an aryl group positioned as in

molindone. It might be conjectured that the proton on the protonated amino group in

these compounds H-bonds with the electrons of the carbonyl oxygen atom.

Molindone Hydrochloride.

Molindone hydrochloride (Moban) is about as potent an antipsychotic as trifluoperazine.

Overall, side effects resemble those of the phenothiazines.

Benzamides:

The benzamides evolved from observations that the gastroprokinetic and antiemetic

agent, metoclopramide, has antipsychotic activity related to D2 receptor block. It was

hoped that the group might yield compounds with diminished EPS liability.

An H-bond between the amido H and the unshared electrons of the methoxyl group to

generate a pseudo ring is considered important for antipsychotic activity in these

compounds.

When the protonated amine is superimposed on that of protonated DA, this pseudo ring

would superimpose on DA’s aromatic ring. These features can be seen in sulpiride and

remoxipride.

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Remoxipride (Roxiam).

Remoxipride is a D2 receptor blocker. It is as effective as haloperidol with fewer EPS and

autonomic side effects. Negative symptoms of schizophrenia are diminished.

The drug is classed as an atypical antipsychotic. Life-threatening aplastic anemia was

reported with its use, which prompted its withdrawal from the market.

Antimanic Agents:

Lithium Salts:

The lithium salts used in the United States are the carbonate (tetrahydrate) and the citrate.

Lithium chloride is not used because of its hygroscopic nature and because it is more

irritating than the carbonate or citrate to the GI tract.

The active species in these salts is the lithium ion. The classic explanation for its

antimanic activity is that it resembles the sodium ion (as well as potassium, magnesium,

and calcium ions) and can occupy the sodium pump. Unlike the sodium ion, it cannot

maintain membrane potentials

Accordingly, it might prevent excessive release of NTs (e.g., DA) that characterize the

manic state.

Lithium reduces signal transduction through the phosphatidylinositol signaling pathway

by uncompetitive inhibition of inositol phosphatase. As a result, the pool of inositol

available for the resynthesis of phosphatidylinositol-4,5-bisphosphate (PIP2) is depleted,

the cellular levels of PIP2 is decreased, thereby, enzymatic formation of the second

messengers is reduced.

The indications for lithium salts are acute mania (often with a potent neuroleptic agent for

immediate control, because lithium is slow to take effect) and as a prophylactic to prevent

occurrence of the mania of bipolar manic–depressive illness.

It works to stabilize the mood and reduce extremes in behavior by restoring the balance

of certain natural substances (neurotransmitters) in the brain.

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Question: Explain, How psychosis produced by phencyclidine (NMDA-antagonist) and

several central anticholinergic drugs?