SAR of phenothiazines MCQs With Answer

Introduction: The structure-activity relationship (SAR) of phenothiazines is vital for B.Pharm students studying antipsychotic pharmacology and medicinal chemistry. Understanding how modifications to the tricyclic phenothiazine core, substituents at positions 2 and 7, and the nature and length of the side chain (aliphatic, piperidine, piperazine) alter dopamine D2 affinity, sedative, anticholinergic and extrapyramidal side-effect profiles helps predict clinical effects of drugs like chlorpromazine, trifluoperazine and thioridazine. Key concepts include electron-withdrawing groups, lipophilicity, basic tertiary amine spacing and metabolic pathways. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. Which structural feature defines the core scaffold of phenothiazines?

• A fused tricyclic ring system containing sulfur and nitrogen atoms
• A benzodiazepine-like seven-membered ring
• A monocyclic aromatic ring with a sulfone group
• A steroid-like four-ring backbone

Correct Answer: A fused tricyclic ring system containing sulfur and nitrogen atoms

Q2. In phenothiazine SAR, adding an electron-withdrawing group at the 2-position typically results in:

• Decreased antipsychotic potency
• Increased antipsychotic potency
• Loss of blood-brain barrier penetration
• Increased metabolic stability without potency change

Correct Answer: Increased antipsychotic potency

Q3. The typical distance (number of carbon atoms) between the ring nitrogen and the aliphatic tertiary amine required for optimal D2 antagonism is:

• One carbon atom
• Two carbon atoms
• Three carbon atoms
• Five carbon atoms

Correct Answer: Three carbon atoms

Q4. Which side-chain class of phenothiazines is most associated with higher extrapyramidal side effects (EPS) due to stronger D2 antagonism?

• Aliphatic side chains
• Piperidine side chains
• Piperazine side chains
• Quaternary ammonium side chains

Correct Answer: Piperazine side chains

Q5. Chlorpromazine belongs to which side-chain class of phenothiazines?

• Piperazine class
• Piperidine class
• Aliphatic class
• Quinazoline class

Correct Answer: Aliphatic class

Q6. Introduction of a halogen at the 7-position of phenothiazines generally causes:

• Decrease in lipophilicity and potency
• Increase in potency and lipophilicity
• Conversion to an antihistamine only
• Complete loss of D2 affinity

Correct Answer: Increase in potency and lipophilicity

Q7. Which metabolic pathway is most commonly involved in modifying the side chain of phenothiazines?

• Aromatic nitration
• N-dealkylation
• β-oxidation
• Glycosylation

Correct Answer: N-dealkylation

Q8. Piperidine-substituted phenothiazines (e.g., thioridazine) are typically characterized by:

• High potency with prominent EPS
• Low potency with prominent anticholinergic effects
• Pure antihistaminic action without antipsychotic effect
• Absence of cardiac effects

Correct Answer: Low potency with prominent anticholinergic effects

Q9. Which phenothiazine is commonly used as an antiemetic rather than a primary antipsychotic?

• Trifluoperazine
• Prochlorperazine
• Fluphenazine
• Thioproperazine

Correct Answer: Prochlorperazine

Q10. Increasing lipophilicity of phenothiazines generally affects CNS penetration by:

• Reducing blood-brain barrier penetration
• Enhancing blood-brain barrier penetration
• No effect on CNS penetration
• Causing active efflux transport into brain

Correct Answer: Enhancing blood-brain barrier penetration

Q11. Replacement of the aliphatic tertiary amine by a quaternary ammonium in phenothiazines typically results in:

• Improved CNS penetration
• Reduced CNS penetration and primarily peripheral action
• Increased oral bioavailability
• Higher D2 affinity and more EPS

Correct Answer: Reduced CNS penetration and primarily peripheral action

Q12. Which functional change to the phenothiazine core tends to reduce antipsychotic activity?

• Maintaining the S and N in the tricyclic core
• Oxidation of sulfur to sulfoxide while keeping the rest unchanged
• Adding electron-withdrawing group at 2-position
• Optimizing three-carbon side-chain spacing

Correct Answer: Oxidation of sulfur to sulfoxide while keeping the rest unchanged

Q13. Which phenotype correlates with tertiary aliphatic side-chain phenothiazines (e.g., chlorpromazine)?

• High potency, pronounced EPS
• Low potency, strong sedation and anticholinergic effects
• Purely antiemetic with no CNS effects
• Only α2 agonism without D2 effects

Correct Answer: Low potency, strong sedation and anticholinergic effects

Q14. The primary pharmacological target responsible for antipsychotic efficacy of phenothiazines is:

• Histamine H1 receptor antagonism
• Dopamine D2 receptor antagonism
• Muscarinic M3 receptor agonism
• Serotonin 5-HT3 receptor antagonism

Correct Answer: Dopamine D2 receptor antagonism

Q15. A bulky substituent at the 10-position of phenothiazines is most likely to:

• Enhance D2 receptor binding dramatically
• Sterically hinder receptor binding and reduce potency
• Convert the molecule to an opioid agonist
• Increase water solubility without pharmacological change

Correct Answer: Sterically hinder receptor binding and reduce potency

Q16. Which modification usually increases antihistaminic (H1) activity in phenothiazines?

• Introduction of bulky polar groups that lower lipophilicity
• Aliphatic side chains and increased lipophilicity
• Removing the tertiary amine
• Adding a strong electron-donating group at position 2

Correct Answer: Aliphatic side chains and increased lipophilicity

Q17. Which phenothiazine structural class tends to produce the least extrapyramidal side effects?

• Piperazine derivatives
• Piperidine derivatives
• Aliphatic derivatives
• Quinazoline derivatives

Correct Answer: Aliphatic derivatives

Q18. Which of the following is a common clinical adverse effect associated with strong α1-adrenergic blockade by phenothiazines?

• Hypotension and orthostatic dizziness
• Hyperthermia
• Urinary retention due to α2 agonism
• Excessive weight loss

Correct Answer: Hypotension and orthostatic dizziness

Q19. Trifluoperazine is best classified as which type of phenothiazine derivative?

• Aliphatic derivative
• Piperidine derivative
• Piperazine derivative
• Quaternary ammonium derivative

Correct Answer: Piperazine derivative

Q20. Which SAR principle explains why tertiary amines in phenothiazines are important for receptor binding?

• Tertiary amines increase water solubility only
• Tertiary amines are protonated at physiological pH and form ionic interactions with receptor sites
• Tertiary amines prevent metabolism completely
• Tertiary amines convert the drug to an antagonist of serotonin receptors

Correct Answer: Tertiary amines are protonated at physiological pH and form ionic interactions with receptor sites

Q21. Which structural modification is typically used to increase peripheral selectivity and reduce CNS side effects of phenothiazines?

• Adding lipophilic halogens
• Converting tertiary amine to quaternary ammonium
• Shortening the side chain to one carbon
• Removing the sulfur atom from the tricyclic core

Correct Answer: Converting tertiary amine to quaternary ammonium

Q22. Which metabolic transformation of the phenothiazine sulfur atom can alter pharmacological activity?

• Sulfation to form sulfate esters
• Oxidation to sulfoxide or sulfone
• Direct methylation of sulfur
• Glucuronidation at sulfur atom

Correct Answer: Oxidation to sulfoxide or sulfone

Q23. Perphenazine is generally considered to have which clinical profile compared to chlorpromazine?

• Higher potency with more EPS and less sedation
• Lower potency with more anticholinergic effects
• No antipsychotic activity
• Only antihypertensive effects

Correct Answer: Higher potency with more EPS and less sedation

Q24. Which physicochemical property most strongly influences a phenothiazine’s ability to cross the blood-brain barrier?

• Molecular chirality
• Lipophilicity and degree of ionization
• Number of aromatic rings only
• Presence of carbohydrate moieties

Correct Answer: Lipophilicity and degree of ionization

Q25. Which clinical risk is particularly associated with thioridazine at high doses?

• Severe hepatotoxicity only
• QT prolongation and cardiac arrhythmias
• Renal failure due to crystal formation
• Immunosuppression leading to infections

Correct Answer: QT prolongation and cardiac arrhythmias

Q26. Which substitution pattern is commonly associated with increased D2 receptor selectivity in phenothiazines?

• Electron-donating groups at 2-position
• Electron-withdrawing groups at 2-position and halogen at 7-position
• Removal of the side chain completely
• Introduction of bulky polar groups at all positions

Correct Answer: Electron-withdrawing groups at 2-position and halogen at 7-position

Q27. N-dealkylation of phenothiazines typically results in:

• Formation of more lipophilic active metabolites
• Production of less active or inactive metabolites
• Immediate conversion to glucuronide conjugates only
• Enhancement of D2 affinity

Correct Answer: Production of less active or inactive metabolites

Q28. Which receptor blockade by phenothiazines contributes most to anticholinergic side effects?

• Dopamine D2 receptor antagonism
• Muscarinic M1 receptor antagonism
• Beta-adrenergic receptor antagonism
• Serotonin 5-HT2A antagonism

Correct Answer: Muscarinic M1 receptor antagonism

Q29. A structure with a piperazine side chain is likely to show which of the following relative properties?

• Lower D2 affinity than aliphatic derivatives
• Higher D2 affinity and greater risk of EPS
• No CNS activity due to polarity
• Selective H2 receptor antagonism

Correct Answer: Higher D2 affinity and greater risk of EPS

Q30. Which phenothiazine is best known for its strong sedative and antihistaminic properties due to its structure?

• Chlorpromazine
• Fluphenazine
• Trifluoperazine
• Haloperidol

Correct Answer: Chlorpromazine

Q31. The presence of which moiety in the side chain tends to reduce anticholinergic effects relative to aliphatic derivatives?

• Piperazine ring
• Piperidine ring
• Long alkyl chain with quaternary nitrogen
• Benzylic hydroxyl group

Correct Answer: Piperazine ring

Q32. Which receptor interactions of phenothiazines explain their antihistaminic and sedative effects?

• H1 receptor antagonism
• D2 receptor agonism
• 5-HT1A receptor agonism
• M2 receptor antagonism only

Correct Answer: H1 receptor antagonism

Q33. Which chemical transformation would most likely reduce the basicity of the side-chain amine in a phenothiazine?

• Alkylation to a tertiary amine
• Acylation to form an amide
• Converting amine to a more basic guanidine
• Reducing an amide to an amine

Correct Answer: Acylation to form an amide

Q34. Which clinical use of phenothiazines exploits their dopamine D2 antagonism aside from antipsychotic therapy?

• Antihypertensive therapy
• Antiemetic treatment for nausea and vomiting
• Antiviral therapy
• Anticoagulation

Correct Answer: Antiemetic treatment for nausea and vomiting

Q35. Which structural change commonly increases potency but also the risk of extrapyramidal symptoms?

• Conversion to quaternary ammonium
• Introduction of a piperazine side chain
• Shortening side chain to one carbon
• Adding polar sugar moiety

Correct Answer: Introduction of a piperazine side chain

Q36. Which phenothiazine adverse effect is largely attributed to prolonged D2 blockade in nigrostriatal pathways?

• Hypotension
• Extrapyramidal symptoms and tardive dyskinesia
• Hypoglycemia
• Bronchospasm

Correct Answer: Extrapyramidal symptoms and tardive dyskinesia

Q37. Which substituent change at the 2-position would you predict to increase receptor affinity in most phenothiazines?

• Adding a nitro or trifluoromethyl group (electron-withdrawing)
• Adding a methoxy group (electron-donating)
• Removing substituents entirely
• Introducing a bulky polar sugar

Correct Answer: Adding a nitro or trifluoromethyl group (electron-withdrawing)

Q38. Which clinical property is often reduced by conversion of a tertiary amine to its N-oxide?

• Hydrophilicity only
• CNS penetration and receptor binding
• Hepatic metabolism via CYP450
• Ability to form salts

Correct Answer: CNS penetration and receptor binding

Q39. Why are phenothiazines formulated as salts (e.g., hydrochloride salts) for oral administration?

• To convert them to quaternary ammonium permanently
• To improve water solubility and stability for dosage forms
• To eliminate all side effects
• To make them inactive prodrugs

Correct Answer: To improve water solubility and stability for dosage forms

Q40. Which testable SAR observation differentiates high-potency from low-potency phenothiazines?

• High-potency agents usually have piperazine side chains and less anticholinergic activity
• High-potency agents always have larger aliphatic side chains and more sedation
• Low-potency agents have stronger D2 blockade than high-potency ones
• No correlation exists between side-chain and potency

Correct Answer: High-potency agents usually have piperazine side chains and less anticholinergic activity

Q41. Which phenothiazine metabolite formation could reduce central activity by increasing polarity?

• N-dealkylated metabolite
• Formation of a methylated tertiary amine
• Replacement of sulfur by carbon
• Formation of an internal ether linkage

Correct Answer: N-dealkylated metabolite

Q42. Which adverse effect profile is typically lower with piperazine derivatives compared to aliphatic derivatives?

• Extrapyramidal symptoms (EPS)
• Anticholinergic effects and sedation
• Cardiac arrhythmias
• QT prolongation exclusively

Correct Answer: Anticholinergic effects and sedation

Q43. Which experimental modification would you predict to increase selectivity for D2 over H1 receptors?

• Increasing overall lipophilicity indiscriminately
• Introducing polar substituents that reduce H1 affinity while retaining D2 interactions
• Removing the tertiary amine
• Adding larger bulky aromatic groups at any position

Correct Answer: Introducing polar substituents that reduce H1 affinity while retaining D2 interactions

Q44. Which clinical monitoring is most relevant when prescribing certain phenothiazines known to prolong QT interval?

• Regular liver enzyme panels only
• ECG monitoring for QT prolongation
• Peak inspiratory flow measurement
• Serum potassium measurement only on day one

Correct Answer: ECG monitoring for QT prolongation

Q45. In medicinal chemistry terms, the pharmacophore for antipsychotic activity in phenothiazines includes:

• An aromatic ring only and no basic centers
• A tricyclic heterocyclic core, a spacer (usually 3 atoms) and a basic tertiary amine
• Only a basic quaternary ammonium moiety without aromatic rings
• A carbohydrate-linked peptide chain

Correct Answer: A tricyclic heterocyclic core, a spacer (usually 3 atoms) and a basic tertiary amine

Q46. Which laboratory technique would most directly confirm N-dealkylation metabolites of a phenothiazine in plasma?

• Thin-layer chromatography without standards
• Mass spectrometry coupled with liquid chromatography (LC-MS)
• pH titration curve analysis only
• Simple UV-Vis spectroscopy without separation

Correct Answer: Mass spectrometry coupled with liquid chromatography (LC-MS)

Q47. For structure-based design, which atomic interaction is most exploited between the phenothiazine tertiary amine and the dopamine receptor?

• Hydrophobic π–π stacking only
• Ionic interaction between protonated tertiary amine and acidic residue in receptor
• Covalent bond formation with receptor cysteines
• Metal chelation with receptor-bound iron

Correct Answer: Ionic interaction between protonated tertiary amine and acidic residue in receptor

Q48. Which physical-chemical property modification could reduce peripheral anticholinergic side effects while maintaining central D2 antagonism?

• Large increase in peripheral polarity preventing BBB crossing
• Designing prodrugs that preferentially release active drug in the CNS
• Complete removal of aromatic rings
• Conversion to a permanently charged quaternary ammonium that crosses BBB more easily

Correct Answer: Designing prodrugs that preferentially release active drug in the CNS

Q49. Which phenothiazine is historically known as the prototypical antipsychotic and introduced many SAR concepts?

• Chlorpromazine
• Ibuprofen
• Diazepam
• Risperidone

Correct Answer: Chlorpromazine

Q50. In designing safer phenothiazine derivatives, medicinal chemists most often aim to:

• Increase non-selective receptor binding to maximize effects
• Enhance D2 selectivity while minimizing H1, α1 and muscarinic off-target interactions
• Eliminate the tertiary amine to increase potency
• Make compounds permanently lipophilic to increase half-life

Correct Answer: Enhance D2 selectivity while minimizing H1, α1 and muscarinic off-target interactions

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