Podcast
Questions and Answers
What is the order of potency based on the position of substituents on the ring?
What is the order of potency based on the position of substituents on the ring?
What effect does shortening the three-carbon alkyl side chain have on neuroleptic activity?
What effect does shortening the three-carbon alkyl side chain have on neuroleptic activity?
What type of amino function is required for maximum activity?
What type of amino function is required for maximum activity?
How does α-carbon substitution affect activity?
How does α-carbon substitution affect activity?
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What happens to the activity with γ-carbon substitution by a methyl group?
What happens to the activity with γ-carbon substitution by a methyl group?
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What characteristic is shared by the chlorpromazine compound?
What characteristic is shared by the chlorpromazine compound?
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What is a consequence of alkylation of the amino group with larger groups than methyl?
What is a consequence of alkylation of the amino group with larger groups than methyl?
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The effectiveness of substituent effects indicates what about the interaction with the protonated amino group?
The effectiveness of substituent effects indicates what about the interaction with the protonated amino group?
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Which antipsychotic drug class is characterized by the presence of thiothixenes?
Which antipsychotic drug class is characterized by the presence of thiothixenes?
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What is one of the key structure-activity relationships (SARs) found in chlorpromazines?
What is one of the key structure-activity relationships (SARs) found in chlorpromazines?
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The butyrophenone class of antipsychotics is primarily known for its action on which receptor?
The butyrophenone class of antipsychotics is primarily known for its action on which receptor?
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Which of the following is NOT associated with the structure-activity relationships of antipsychotics?
Which of the following is NOT associated with the structure-activity relationships of antipsychotics?
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In structure-activity relationships, increased lipophilicity in antipsychotic drugs is generally associated with which property?
In structure-activity relationships, increased lipophilicity in antipsychotic drugs is generally associated with which property?
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Which of the following chemical structures is typically featured in the diarylazepine class of antipsychotic agents?
Which of the following chemical structures is typically featured in the diarylazepine class of antipsychotic agents?
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Which property is significant in determining the pharmacokinetics of antipsychotic drugs?
Which property is significant in determining the pharmacokinetics of antipsychotic drugs?
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The presence of which structural feature is commonly associated with the benzisoxazole antipsychotic class?
The presence of which structural feature is commonly associated with the benzisoxazole antipsychotic class?
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What is the optimal chain length between two nitrogen atoms in the structure activity relationship of phenothiazines?
What is the optimal chain length between two nitrogen atoms in the structure activity relationship of phenothiazines?
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Which position is deemed best for substitution on the phenothiazine ring?
Which position is deemed best for substitution on the phenothiazine ring?
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In the structure of phenothiazines, what indicates that an amine is tertiary?
In the structure of phenothiazines, what indicates that an amine is tertiary?
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Which of the following compounds is a hydrochloride form of phenothiazine?
Which of the following compounds is a hydrochloride form of phenothiazine?
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What structural feature is common in the phenothiazine derivatives mentioned?
What structural feature is common in the phenothiazine derivatives mentioned?
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Which of the following statements about R groups in phenothiazines is correct?
Which of the following statements about R groups in phenothiazines is correct?
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Which phenothiazine is often used as an antipsychotic medication?
Which phenothiazine is often used as an antipsychotic medication?
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What type of nitrogen atom is typically found in tertiary amines relevant to phenothiazines?
What type of nitrogen atom is typically found in tertiary amines relevant to phenothiazines?
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Which compound is a derivative of chlorpromazine?
Which compound is a derivative of chlorpromazine?
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What aspect of phenothiazines is indicated by substituents at the 2-position?
What aspect of phenothiazines is indicated by substituents at the 2-position?
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Study Notes
Antipsychotic Drugs
- Antipsychotic drugs treat psychoses, affecting approximately 1% of the population.
- Psychoses are psychogenic mental disorders involving a loss of contact with reality.
- Common psychotic disorders include schizophrenia, manic phase of bipolar disorder, and acute idiopathic psychotic illness.
- Schizophrenia is characterized by altered perception, thinking, communication, social functioning, and attention.
- Symptoms of schizophrenia are categorized as positive (delusions, hallucinations) or negative (flat affect, apathy).
- Cognitive dysfunction can also occur.
Dopamine Hypothesis
- Drugs that increase dopamine neurotransmission (e.g., levodopa, amphetamines, apomorphine) can exacerbate schizophrenia.
- Dopamine receptor density is increased in certain brain regions of untreated schizophrenics.
- Many antipsychotic drugs block postsynaptic D₂ receptors in the central nervous system (CNS) to reduce dopamine activity.
- Successful treatment of schizophrenic patients may change the amount of dopamine-related substances in plasma and urine.
- The figure illustrates dopamine's synthesis, breakdown, and its relationship to the disorder.
Role of Dopamine in the Development of Psychosis
- Dopamine has four major pathways affecting the brain: mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular.
- Mesolimbic pathway is hyperactive in schizophrenia, mediating positive symptoms (delusions, hallucinations).
- Mesocortical pathway is underactive in schizophrenia, contributing to negative symptoms (loss of motivation, social withdrawal).
- Nigrostriatal pathway is involved in motor function; dopamine deficiency leads to dystonia and parkinsonian symptoms, excess leads to hyperkinetic movements(tics, dyskinesias).
- Tuberoinfundibular pathway controls prolactin secretion; dopamine blockade can cause hyperprolactinemia (elevated prolactin levels), which leads to gynecomastia (breast development in males) and sexual dysfunction.
Dopamine Receptors
- Five primary dopamine receptors (D1, D2, D3, D4, D5).
- D2 receptors are the most clinically important targets of antipsychotic drugs.
- Antipsychotic action is thought to result from dopamine receptor blockade (especially D2) in the mesolimbic and mesocortical pathways.
- Side effects of antipsychotic drugs (extrapyramidal symptoms) correlate with antagonism at D₂ receptors in the nigrostriatal pathway.
- Antipsychotic drugs block dopamine's inhibitory effect on prolactin release from the pituitary gland via the tuberoinfundibular pathway, which can lead to hyperprolactinemia.
First-Generation ("Typical") Antipsychotics
- Block D2 receptors in diverse brain areas, including those involved in both positive and negative symptoms.
- Blockade in mesolimbic pathway is helpful in reducing delusions and hallucinations.
- Blockade in mesocortical pathway can worsen negative symptoms such as lack of motivation.
- Blockade in nigrostriatal pathway may cause Parkinson's-like symptoms (extrapyramidal side effects).
- Blockade in tuberoinfundibular pathway leads to hyperprolactinemia, impacting sexual and reproductive functions.
- These are differentiated by potency, some have greater affinity for D2 receptors which lead to higher potency and a greater effect.
- Side effects can include dizziness, blurred vision, sedation, and weight gain.
Second-Generation ("Atypical") Antipsychotics
- Block both dopamine D2 and serotonin 2A receptors.
- This dual action may explain their potential reduced risk of extrapyramidal side effects compared to typical antipsychotics.
- Modest D2 blockade in combination with serotonin receptor blockade can decrease both positive and negative symptoms better.
- Also target other receptors, such as histamine, alpha-1-adrenergic, and muscarinic receptors leading to varied side effects and may cause weight gain, sedation and hypotension.
Classification of Antipsychotics
- Antipsychotic drugs are classified as typical & atypical
- Typical antipsychotics include phenothiazines, butyrophenones, and thioxanthines.
- Atypical antipsychotics include clozapine, risperidone, olanzapine, and quetiapine.
Specific Antipsychotics (Phenothiazines/Thioxanthenes, etc.)
- Detailed information, specific to each individual antipsychotic drug (structures, chemical properties, clinical uses, side effects), is provided for the phenothiazines and thiothixenes.
Structure-Activity Relationships (SAR)
- Detailed relationships between the chemical structure and pharmacological activity (e.g., antipsychotic effects) of antipsychotic drugs (including data/figures).
Alkyl Side Chain
- The three-carbon chain between the 10th position and the amino nitrogen is critical for neuroleptic activity.
- Shortening or lengthening the chain reduces potency but may modulate other effects, such as antihistamine and anticholinergic effects.
- Substitutions on the alkyl chain can further modify activity.
Amino Group
- For maximum activity, the amino group must be tertiary.
- Primary and secondary amino groups have reduced potency compared to tertiary ones.
- Alkylation of the amino group with larger substituents can diminish antipsychotic activity.
Phenothiazine Alkyl Side Chain Derivatives
- The detailed information of specific phenothiazines like chlorpromazine (Thorazine), promazine (Sparine), and triflupromazine (Vesprin), including their clinical uses, bioavailability, and potential side effects is covered.
Thioxanthenes
- Thioxanthenes, particularly thiothixene (Navane), differ structurally from phenothiazines but have similar pharmacological properties, particularly when it comes to antipsychotic effects and side effects.
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Description
This quiz explores antipsychotic drugs used in treating psychoses like schizophrenia. It covers the symptoms, the dopamine hypothesis, and how these drugs function by affecting dopamine neurotransmission. Test your knowledge on the mechanisms and effects of antipsychotic medications.
