Antipsychotic drugs, also known as neuroleptics, are medications used to treat psychiatric disorders

such as schizophrenia, bipolar disorder, and severe depression. They can be categorized into two main
classes based on their chemical structure and mode of action:

General classification:
Typical antipsychotics: These were the first generation of antipsychotic drugs, also known as
conventional or traditional antipsychotics. They work by blocking dopamine receptors in the brain,
which reduces the activity of dopamine and helps to control symptoms such as hallucinations and
delusions. Examples of typical antipsychotics include haloperidol, chlorpromazine, and fluphenazine.

Atypical antipsychotics: These are the second generation of antipsychotic drugs, also known as newer or
second-generation antipsychotics. They also work by blocking dopamine receptors, but they also affect
other neurotransmitters such as serotonin and norepinephrine. Atypical antipsychotics are generally
considered to have fewer side effects than typical antipsychotics. Examples of atypical antipsychotics
include risperidone, quetiapine, and olanzapine.

Chemical classification:
Antipsychotic drugs, also known as neuroleptics, can be classified into two main chemical categories:

Phenothiazines: This is the largest class of antipsychotic drugs and includes medications such as
chlorpromazine and perphenazine. Phenothiazines have a tricyclic chemical structure and work by
blocking dopamine receptors in the brain.

Non-phenothiazines: This class of antipsychotic drugs includes medications such as haloperidol,

risperidone, and clozapine. Non-phenothiazines have a different chemical structure than phenothiazines
and can be further divided into two subcategories:

Butyrophenones: This includes medications such as haloperidol and droperidol, which have a similar
chemical structure to phenothiazines and work by blocking dopamine receptors in the brain.

Atypical antipsychotics: This includes medications such as risperidone, clozapine, and quetiapine, which
have a different chemical structure than phenothiazines and butyrophenones. Atypical antipsychotics
work by blocking dopamine receptors as well as other neurotransmitter receptors, such as serotonin
and norepinephrine.
The dopamine hypothesis of psychosis suggests that an overactivity of the dopamine system in the brain
is a primary cause of psychotic disorders, such as schizophrenia.

Dopamine is a neurotransmitter that plays a key role in regulating movement, motivation, and reward.
In the brain, dopamine is produced by a group of neurons known as the dopaminergic system. It is
believed that when there is an excess of dopamine in certain areas of the brain, it can lead to
hallucinations, delusions, and other symptoms of psychosis.

The hypothesis is based on the observation that antipsychotic medications, which are used to treat
psychotic symptoms, work by blocking dopamine receptors in the brain. This suggests that excessive
dopamine activity may be responsible for the symptoms of psychosis.

However, the dopamine hypothesis of psychosis is not a complete explanation for the disorder. While it
is true that drugs that increase dopamine levels, such as amphetamines, can produce psychotic
symptoms, not all people with schizophrenia have elevated dopamine levels. In addition, not all
antipsychotic medications work by blocking dopamine receptors, and some people with schizophrenia
do not respond to these medications.

Despite its limitations, the dopamine hypothesis of psychosis has provided a useful framework for
understanding the neurobiology of psychotic disorders and has led to the development of effective
treatments for these conditions.

Describe the structural modifications of the

phenothiazines that resulted in increased
antipsychotic activity?
Phenothiazines are a class of antipsychotic medications that have been used for many years to treat
various mental health conditions, including schizophrenia and bipolar disorder. Over time, researchers
have modified the chemical structure of phenothiazines to improve their efficacy and reduce their side
effects.

Here are some structural modifications of phenothiazines that have resulted in increased antipsychotic
activity:
Alkylation of the nitrogen atom: By adding an alkyl group to the nitrogen atom of the phenothiazine
molecule, researchers have been able to increase the lipophilicity (fat solubility) of the compound. This
improves its ability to cross the blood-brain barrier and reach its target site in the brain.

Substitution of the phenothiazine ring: By substituting one or more atoms or groups on the
phenothiazine ring, researchers have been able to modify the pharmacological properties of the
compound. For example, the addition of a chlorine atom at position 2 of the ring (chlorpromazine)
increases its potency as an antipsychotic.

Introduction of a thioxanthene ring: Thioxanthenes are structurally related to phenothiazines but have a
different ring structure. By introducing a thioxanthene ring into the phenothiazine structure, researchers
have created compounds with increased potency and reduced side effects.

Reduction of side chain length: By reducing the length of the side chain attached to the nitrogen atom of
the phenothiazine molecule, researchers have been able to reduce the risk of side effects such as
sedation and hypotension. This modification has resulted in the development of "atypical"
antipsychotics such as risperidone and olanzapine.

Overall, these structural modifications have allowed researchers to develop antipsychotic medications
with improved efficacy and tolerability, which have been instrumental in the treatment of various
mental health conditions.

Promethazine and chlorpromazine are both medications that belong to the phenothiazine class of
antipsychotics. However, they have different uses and mechanisms of action. Here's a comparison
between the two:

Uses:

Promethazine is primarily used to treat allergies, nausea, and vomiting, while also having mild sedative
effects. It can also be used as a preoperative medication to reduce anxiety and provide sedation.

Chlorpromazine, on the other hand, is primarily used as an antipsychotic medication to treat

schizophrenia, bipolar disorder, and other psychotic disorders. It can also be used to treat severe nausea
and vomiting, as well as anxiety.
Mechanism of Action:

Promethazine acts on histamine receptors in the brain, blocking the effects of histamine and reducing
symptoms of allergies and nausea. It also has mild sedative effects.

Chlorpromazine works by blocking dopamine receptors in the brain, which can help reduce symptoms of
psychosis and mania. It also has anti-serotonergic, anti-adrenergic, and anti-histaminergic effects.

Side Effects:

Promethazine can cause drowsiness, dizziness, dry mouth, blurred vision, constipation, and difficulty
urinating. It can also cause more serious side effects, such as seizures, confusion, and respiratory
depression.

Chlorpromazine can cause similar side effects to promethazine, as well as weight gain, sexual
dysfunction, and movement disorders, such as tardive dyskinesia.

Overall, promethazine and chlorpromazine are two different medications with different uses and
mechanisms of action. While both drugs can cause similar side effects, they are used to treat different
conditions and should only be taken under the guidance of a healthcare provider.

Describe the SAR of Phenothiazine derived antipsychotic drug

The structure-activity relationship (SAR) of phenothiazine-derived antipsychotic
drugs involves modifications to the chemical structure of the phenothiazine
molecule in order to optimize its therapeutic properties.

Phenothiazines have a tricyclic structure consisting of two six-membered benzene

rings and a seven-membered thiazine ring. The basic structure of phenothiazine
antipsychotic drugs can be modified in several ways to improve their potency,
selectivity, and pharmacokinetic properties. Some common modifications include:

Substitution of the phenothiazine ring: The aromatic rings of the phenothiazine

molecule can be substituted with various groups, such as alkyl, halogen, or nitro
groups. These substitutions can affect the drug's potency, binding affinity, and
selectivity for certain receptors.

Modification of the side chain: The side chain of the phenothiazine molecule can
be modified by adding or removing substituents, such as alkyl or hydroxyl groups.
These modifications can affect the drug's solubility, metabolic stability, and
pharmacokinetics.

Addition of functional groups: Functional groups, such as sulfonamide or amide

groups, can be added to the phenothiazine molecule to improve its
pharmacokinetic properties, such as bioavailability and half-life.

Stereochemistry: The stereochemistry of the phenothiazine molecule can affect its

pharmacological properties, such as receptor selectivity and potency.
Modifications to the stereochemistry can result in enantiomers with different
pharmacological profiles.

Overall, the SAR of phenothiazine-derived antipsychotic drugs is complex and

involves multiple factors, such as receptor binding affinity, pharmacokinetics, and
metabolic stability. Modifications to the phenothiazine molecule can result in drugs
with improved potency, selectivity, and therapeutic efficacy.

how does substitution of aromatic ring affect potency of

phenothiazine
The substitution of the aromatic ring in phenothiazine can affect its potency as an
antipsychotic drug. This is because the substitution can affect the drug's binding
affinity for its target receptors, such as dopamine and serotonin receptors, which
are believed to be involved in the pathophysiology of schizophrenia and other
psychotic disorders.
The potency of phenothiazine can be enhanced by substituting the aromatic ring
with electron-withdrawing groups, such as halogens (e.g., chloro, fluoro, and
bromo), nitro groups, or carbonyl groups. These substitutions can increase the
electron density of the ring, which can enhance the drug's binding affinity for the
dopamine D2 receptor, the primary target of antipsychotic drugs. For example,
chlorpromazine, which has a chloro substituent on the aromatic ring, is more
potent than promethazine, which lacks a chloro substituent.

Conversely, substitution with electron-donating groups, such as alkyl or alkoxy

groups, can decrease the potency of phenothiazine by reducing the electron density
of the ring and weakening the drug's binding affinity for the target receptors. For
example, the potency of promethazine, which has an alkyl group substitution, is
lower than that of chlorpromazine.

Overall, the substitution of the aromatic ring in phenothiazine can affect its
potency as an antipsychotic drug by altering its binding affinity for its target
receptors. The specific substituent and its position on the ring can also affect the
drug's pharmacokinetics and side effect profile, which should be carefully
considered in the design of new antipsychotic drugs.