MCQ Quiz: Medicinal Chemistry of Drugs Affecting Antipsychotics

The medicinal chemistry of antipsychotic drugs tracks the evolution of treating psychotic disorders, moving from broad-acting agents to more selective molecules with improved side effect profiles. Understanding the core chemical structures, from the rigid tricyclic phenothiazines to the diverse “atypical” agents, is key to grasping their pharmacology. This quiz will test your knowledge on the structure-activity relationships, pharmacophores, and chemical principles that govern the action of first- and second-generation antipsychotics.

1. The “phenothiazine” chemical class, characterized by a tricyclic structure with a sulfur and nitrogen atom in the central ring, is the backbone of which first-generation antipsychotic?

• a. Haloperidol
• b. Aripiprazole
• c. Chlorpromazine
• d. Olanzapine

Answer: c. Chlorpromazine

2. First-generation antipsychotics (FGAs) exert their primary therapeutic effect by acting as strong antagonists at which receptor?

• a. Serotonin 5-HT2A
• b. Histamine H1
• c. Muscarinic M1
• d. Dopamine D2

Answer: d. Dopamine D2

3. Second-generation antipsychotics (SGAs), like risperidone and olanzapine, are considered “atypical” because they combine D2 antagonism with potent antagonism at which other receptor?

• a. Dopamine D1
• b. Serotonin 5-HT2A
• c. NMDA
• d. GABA-A

Answer: b. Serotonin 5-HT2A

4. Haloperidol is a high-potency first-generation antipsychotic belonging to which chemical class?

• a. Phenothiazine
• b. Thioxanthene
• c. Butyrophenone
• d. Dibenzodiazepine

Answer: c. Butyrophenone

5. The significant sedation seen with low-potency FGAs like chlorpromazine is due to its strong antagonist activity at which receptor?

• a. Dopamine D2
• b. Serotonin 5-HT1A
• c. Histamine H1
• d. Beta-2 adrenergic

Answer: c. Histamine H1

6. The dry mouth, blurred vision, and constipation caused by some antipsychotics are due to their antagonist activity at which receptor?

• a. Alpha-1 adrenergic
• b. Dopamine D4
• c. Serotonin 5-HT2C
• d. Muscarinic cholinergic M1

Answer: d. Muscarinic cholinergic M1

7. From a medicinal chemistry perspective, the lower risk of extrapyramidal symptoms (EPS) with SGAs is attributed to:

• a. Their higher affinity for the D2 receptor.
• b. Their potent 5-HT2A antagonism, which is thought to increase dopamine release in the nigrostriatal pathway.
• c. Their inability to cross the blood-brain barrier.
• d. Their rapid metabolism.

Answer: b. Their potent 5-HT2A antagonism, which is thought to increase dopamine release in the nigrostriatal pathway.

8. Clozapine is an atypical antipsychotic with a unique efficacy profile. It belongs to which chemical class?

• a. Phenothiazine
• b. Butyrophenone
• c. Dibenzodiazepine
• d. Benzisoxazole

Answer: c. Dibenzodiazepine

9. The chemical structure of aripiprazole is unique because it allows the drug to act as a:

• a. Full D2 receptor agonist
• b. Pure D2 receptor antagonist
• c. D2 receptor partial agonist
• d. Selective serotonin reuptake inhibitor

Answer: c. D2 receptor partial agonist

10. Adding a long-chain fatty acid ester to the hydroxyl group of an antipsychotic (e.g., haloperidol decanoate) is a medicinal chemistry strategy used to create:

• a. An oral, rapid-release formulation.
• b. A long-acting injectable (depot) formulation.
• c. A sublingual formulation.
• d. A more potent drug.

Answer: b. A long-acting injectable (depot) formulation.

11. The “-apine” suffix (as in olanzapine, clozapine, quetiapine) is characteristic of which structural class of atypical antipsychotics?

• a. The “dones”
• b. The “pips”
• c. The dibenzazepine derivatives
• d. The butyrophenones

Answer: c. The dibenzazepine derivatives

12. The orthostatic hypotension caused by some antipsychotics like chlorpromazine and risperidone is due to the blockade of which receptor?

• a. Dopamine D2
• b. Serotonin 5-HT2A
• c. Alpha-1 adrenergic
• d. Muscarinic M1

Answer: c. Alpha-1 adrenergic

13. A key structural feature of the phenothiazine nucleus is its:

• a. Planar, flat shape.
• b. Flexible, linear shape.
• c. Folded, non-planar, tricyclic shape.
• d. Simple, monocyclic shape.

Answer: c. Folded, non-planar, tricyclic shape.

14. A drug’s ability to cause metabolic side effects like weight gain is often linked to its antagonist activity at which receptors?

• a. Dopamine D2 and Muscarinic M1
• b. Histamine H1 and Serotonin 5-HT2C
• c. Alpha-1 and Beta-2
• d. NMDA and GABA

Answer: b. Histamine H1 and Serotonin 5-HT2C

15. The “pharmacophore” for D2 receptor antagonism generally requires:

• a. A basic nitrogen atom.
• b. An aromatic ring system.
• c. A specific distance between the nitrogen and the aromatic ring.
• d. All of the above.

Answer: d. All of the above.

16. The “-idone” suffix (as in risperidone, paliperidone) is characteristic of which structural class of atypical antipsychotics?

• a. Benzisoxazole/benzisothiazole derivatives
• b. Dibenzazepines
• c. Butyrophenones
• d. Dihydroindolones

Answer: a. Benzisoxazole/benzisothiazole derivatives

17. A pharmacist’s understanding of medicinal chemistry allows them to predict a drug’s side effect profile based on its:

• a. Cost
• b. Receptor binding affinities
• c. Brand name
• d. Dosage form

Answer: b. Receptor binding affinities

18. Paliperidone is the major active metabolite of which other antipsychotic?

• a. Olanzapine
• b. Quetiapine
• c. Risperidone
• d. Aripiprazole

Answer: c. Risperidone

19. What is a key chemical property of most antipsychotics that allows them to cross the blood-brain barrier?

• a. They are highly hydrophilic.
• b. They are large peptides.
• c. They are lipophilic.
• d. They are permanently charged ions.

Answer: c. They are lipophilic.

20. The difference between high-potency and low-potency FGAs is that low-potency agents:

• a. Have a lower affinity for the D2 receptor and require higher doses.
• b. Have a higher affinity for the D2 receptor.
• c. Have fewer side effects.
• d. Are more effective.

Answer: a. Have a lower affinity for the D2 receptor and require higher doses.

21. A drug’s three-dimensional structure (stereochemistry) is critical for its interaction with a receptor.

• a. True
• b. False

Answer: a. True

22. The development of SGAs was an attempt to create drugs with:

• a. Only D2 receptor activity.
• b. A more complex receptor binding profile to improve efficacy and reduce side effects.
• c. No receptor activity.
• d. A purely hormonal mechanism.

Answer: b. A more complex receptor binding profile to improve efficacy and reduce side effects.

23. Which functional group is a key part of the butyrophenone class of antipsychotics?

• a. A ketone
• b. An ester
• c. An amide
• d. A carboxylic acid

Answer: a. A ketone

24. The addition of a fluorine atom to a molecule like haloperidol can:

• a. Increase its lipophilicity.
• b. Enhance its potency.
• c. Both a and b.
• d. Neither a nor b.

Answer: c. Both a and b.

25. A pharmacist understanding that olanzapine and clozapine are structurally similar helps them anticipate that they might share which side effect profile?

• a. Low risk of weight gain.
• b. High risk of extrapyramidal symptoms.
• c. High risk of metabolic side effects.
• d. No sedation.

Answer: c. High risk of metabolic side effects.

26. The concept of a “bioisostere,” where one group is replaced by another with similar properties, is a key medicinal chemistry tool used in drug design.

• a. True
• b. False

Answer: a. True

27. The term “structure-activity relationship” (SAR) refers to how modifying a drug’s chemical structure alters its biological effects.

• a. True
• b. False

Answer: a. True

28. Why does adding a long ester chain to haloperidol create a long-acting depot injection?

• a. The ester must be slowly hydrolyzed by enzymes in the body to release the active drug.
• b. The ester makes the drug more water-soluble.
• c. The ester is more potent than the parent drug.
• d. The ester is absorbed faster.

Answer: a. The ester must be slowly hydrolyzed by enzymes in the body to release the active drug.

29. The “piperazine” side chain on some phenothiazines (e.g., fluphenazine) generally confers:

• a. Lower potency and more sedation.
• b. Higher potency and a greater risk of EPS.
• c. Only anticholinergic effects.
• d. No D2 blockade.

Answer: b. Higher potency and a greater risk of EPS.

30. The “aliphatic” side chain on some phenothiazines (e.g., chlorpromazine) generally confers:

• a. Higher potency and less sedation.
• b. Lower potency and more sedation.
• c. No risk of EPS.
• d. A lack of anticholinergic side effects.

Answer: b. Lower potency and more sedation.

31. The basic nitrogen atom found in the side chain of most antipsychotics is crucial for:

• a. Forming a salt to improve water solubility.
• b. Interacting with the D2 receptor.
• c. Both a and b.
• d. Neither a nor b.

Answer: c. Both a and b.

32. The “pips and a rip” mnemonic refers to which group of antipsychotics?

• a. Aripiprazole, Brexpiprazole, Cariprazine
• b. Olanzapine, Clozapine, Quetiapine
• c. Risperidone, Paliperidone, Iloperidone
• d. Haloperidol, Droperidol

Answer: a. Aripiprazole, Brexpiprazole, Cariprazine

33. The chemical property that makes most antipsychotics substrates for CYP450 metabolism is their:

• a. Hydrophilicity
• b. Lipophilicity
• c. Small size
• d. Peptide structure

Answer: b. Lipophilicity

34. Lurasidone is a benzisothiazole derivative that must be taken with food. This counseling point is based on what chemical/pharmaceutical principle?

• a. Its mechanism of action.
• b. Its poor water solubility and the need for bile acids from food to aid absorption.
• c. Its stability in the stomach.
• d. Its receptor binding profile.

Answer: b. Its poor water solubility and the need for bile acids from food to aid absorption.

35. A pharmacist’s knowledge of medicinal chemistry is useful for understanding:

• a. The rationale for a drug’s side effects.
• b. The basis for drug interactions.
• c. The reason for specific counseling points.
• d. All of the above.

Answer: d. All of the above.

36. The “-azine” suffix is characteristic of which class of first-generation antipsychotics?

• a. Butyrophenones
• b. Thioxanthenes
• c. Phenothiazines
• d. Dibenzazepines

Answer: c. Phenothiazines

37. The LogP value is a measure of a drug’s lipophilicity, a key predictor of its ability to cross the BBB.

• a. True
• b. False

Answer: a. True

38. The D2 partial agonism of aripiprazole means it can act as a(n) ____ in low dopamine environments and a(n) ____ in high dopamine environments.

• a. antagonist, agonist
• b. agonist, antagonist
• c. agonist, agonist
• d. antagonist, antagonist

Answer: b. agonist, antagonist

39. The design of atypical antipsychotics is a classic example of medicinal chemists attempting to improve a drug’s:

• a. Potency
• b. Selectivity and safety profile
• c. Cost
• d. Solubility

Answer: b. Selectivity and safety profile

40. The overall goal of medicinal chemistry is to establish a clear relationship between a molecule’s structure and its biological activity.

• a. True
• b. False

Answer: a. True

41. Which of the following is NOT a primary drug target for antipsychotic medications?

• a. Dopamine receptors
• b. Serotonin receptors
• c. The blood-brain barrier
• d. Histamine receptors

Answer: c. The blood-brain barrier

42. The chemical structure of a drug is unrelated to its side effect profile.

• a. True
• b. False

Answer: b. False

43. A pharmacist’s understanding of a drug’s chemistry helps them make more informed clinical decisions.

• a. True
• b. False

Answer: a. True

44. What structural feature allows depot injections to be long-acting?

• a. A large peptide chain.
• b. A long, lipophilic ester side chain.
• c. A positive charge.
• d. A sugar moiety.

Answer: b. A long, lipophilic ester side chain.

45. Which of the following is NOT a chemical class of antipsychotics?

• a. Phenothiazine
• b. Butyrophenone
• c. Benzodiazepine
• d. Dibenzazepine

Answer: c. Benzodiazepine

46. A drug’s pKa determines its degree of ionization at a given pH, which affects its absorption and distribution.

• a. True
• b. False

Answer: a. True

47. The term “bioisostere” refers to substituents or groups with similar physical or chemical properties that produce broadly similar biological properties. This concept is used to:

• a. Design new drugs by modifying existing ones.
• b. Reduce toxicity.
• c. Alter a drug’s pharmacokinetic profile.
• d. All of the above.

Answer: d. All of the above.

48. A key skill for a pharmacist is to be able to recognize drug classes based on common structural features or name suffixes.

• a. True
• b. False

Answer: a. True

49. The overall management of antipsychotic therapy is guided by understanding both the drug’s chemistry and the patient’s clinical needs.

• a. True
• b. False

Answer: a. True

50. The ultimate reason for a pharmacist to learn the medicinal chemistry of antipsychotics is to:

• a. Fundamentally understand how they work to provide safer and more effective patient care.
• b. Pass the medicinal chemistry exam.
• c. Be able to synthesize them in a lab.
• d. Impress your colleagues with your ability to draw chemical structures.

Answer: a. Fundamentally understand how they work to provide safer and more effective patient care.