MCQ Quiz: Medicinal Chemistry of Non-Benzodiazepines

The development of non-benzodiazepine anxiolytics and hypnotics represents a significant medicinal chemistry effort to achieve greater selectivity and improve the side effect profiles of older medications. The Patient Care VII: Brain and Behavior course explores the medicinal chemistry of these agents, highlighting how their unique structures lead to distinct pharmacological actions. This quiz will test your knowledge of the structure-activity relationships (SAR), mechanisms of action, and metabolic pathways of key non-benzodiazepine classes, including the “Z-drugs,” buspirone, and orexin receptor antagonists.

1. The “Z-drugs” (e.g., zolpidem, zaleplon) are structurally distinct from benzodiazepines. However, what is the key similarity in their mechanism of action?

• A. They both irreversibly inhibit the MAO enzyme.
• B. They both bind to the benzodiazepine (BZD) binding site on the GABA-A receptor.
• C. They both act as serotonin 5-HT1A partial agonists.
• D. They both block histamine H1 receptors.

Answer: B. They both bind to the benzodiazepine (BZD) binding site on the GABA-A receptor.

2. The medicinal chemistry goal in developing the Z-drugs was to create molecules with higher selectivity for which GABA-A receptor subunit, primarily associated with sedation?

• A. Alpha-1 (α1) subunit
• B. Alpha-2 (α2) subunit
• C. Alpha-5 (α5) subunit
• D. Gamma (γ) subunit

Answer: A. Alpha-1 (α1) subunit

3. Buspirone has a chemical structure completely unrelated to benzodiazepines. Its anxiolytic effect is primarily mediated by:

• A. Potentiation of GABAergic neurotransmission.
• B. Antagonism of dopamine D2 receptors.
• C. Partial agonism at serotonin 5-HT1A receptors.
• D. Inhibition of serotonin and norepinephrine reuptake.

Answer: C. Partial agonism at serotonin 5-HT1A receptors.

4. Zolpidem belongs to which chemical class, distinguishing it from benzodiazepines?

• A. Imidazopyridine
• B. Pyrazolopyrimidine
• C. Azaspirodecanedione
• D. Cyclopyrrolone

Answer: A. Imidazopyridine

5. The drug flumazenil can reverse the sedative effects of zolpidem. This is possible because:

• A. Flumazenil is a general CNS stimulant.
• B. Flumazenil competitively antagonizes the BZD binding site where zolpidem also acts.
• C. Flumazenil inhibits the metabolism of zolpidem.
• D. Zolpidem is structurally a benzodiazepine.

Answer: B. Flumazenil competitively antagonizes the BZD binding site where zolpidem also acts.

6. Unlike benzodiazepines, buspirone lacks hypnotic, muscle relaxant, and anticonvulsant properties. This is because its chemical structure does not allow it to interact with:

• A. Serotonin receptors.
• B. Dopamine receptors.
• C. The GABA-A receptor complex.
• D. Adrenergic receptors.

Answer: C. The GABA-A receptor complex.

7. Ramelteon is a hypnotic whose tricyclic structure was designed to mimic which endogenous substance?

• A. GABA
• B. Serotonin
• C. Orexin
• D. Melatonin

Answer: D. Melatonin

8. The medicinal chemistry strategy behind orexin receptor antagonists like suvorexant is to promote sleep by:

• A. Enhancing the effects of the inhibitory neurotransmitter GABA.
• B. Blocking the signals of orexin, a wakefulness-promoting neuropeptide.
• C. Directly agonizing melatonin receptors.
• D. Blocking the reuptake of serotonin.

Answer: B. Blocking the signals of orexin, a wakefulness-promoting neuropeptide.

9. Zaleplon, which belongs to the pyrazolopyrimidine class, has a very short half-life. This pharmacokinetic property is a direct result of its chemical structure, which allows for rapid:

• A. Renal excretion without metabolism.
• B. Metabolism, primarily by aldehyde oxidase.
• C. Distribution into fat tissue.
• D. Binding to plasma proteins.

Answer: B. Metabolism, primarily by aldehyde oxidase.

10. What is the key stereochemical relationship between zopiclone and eszopiclone?

• A. They are geometric isomers.
• B. Eszopiclone is the active S-enantiomer of racemic zopiclone.
• C. They are the same molecule.
• D. Eszopiclone is an inactive metabolite of zopiclone.

Answer: B. Eszopiclone is the active S-enantiomer of racemic zopiclone.

11. The lack of cross-tolerance between buspirone and benzodiazepines is a direct result of their:

• A. Identical chemical structures and mechanisms of action.
• B. Completely different chemical structures and mechanisms of action.
• C. Similar metabolic pathways.
• D. Similar oral bioavailability.

Answer: B. Completely different chemical structures and mechanisms of action.

12. The term “non-benzodiazepine” primarily refers to a drug’s:

• A. Clinical indication.
• B. Chemical structure.
• C. Side effect profile.
• D. Cost.

Answer: B. Chemical structure.

13. The selectivity of Z-drugs for the α1 subunit of the GABA-A receptor is the medicinal chemistry basis for their primary use as:

• A. Anxiolytics
• B. Anticonvulsants
• C. Muscle relaxants
• D. Hypnotics

Answer: D. Hypnotics

14. The delayed onset of anxiolytic action for buspirone (weeks) is a clinical consequence of its mechanism, which requires:

• A. Accumulation of the drug to toxic levels.
• B. Downregulation of presynaptic 5-HT1A autoreceptors and other neuroadaptive changes.
• C. Slow conversion to an active metabolite.
• D. Saturation of plasma protein binding sites.

Answer: B. Downregulation of presynaptic 5-HT1A autoreceptors and other neuroadaptive changes.

15. Ramelteon’s mechanism of action involves selective agonism at which two receptors?

• A. D1 and D2
• B. 5-HT1A and 5-HT2A
• C. H1 and H2
• D. MT1 and MT2

Answer: D. MT1 and MT2

16. Which functional group is present in buspirone but absent in benzodiazepines and Z-drugs?

• A. A benzene ring
• B. A protonatable amine
• C. An azaspirodecanedione moiety
• D. A halogen

Answer: C. An azaspirodecanedione moiety

17. The primary metabolic pathway for zolpidem and eszopiclone involves which CYP450 enzyme?

• A. CYP2D6
• B. CYP2C19
• C. CYP1A2
• D. CYP3A4

Answer: D. CYP3A4

18. Why would flumazenil be ineffective in reversing an overdose of buspirone?

• A. Buspirone is not a CNS depressant.
• B. Buspirone does not bind to the BZD site on the GABA-A receptor.
• C. Flumazenil is rapidly metabolized.
• D. Buspirone is a more potent agonist than flumazenil.

Answer: B. Buspirone does not bind to the BZD site on the GABA-A receptor.

19. A key principle of medicinal chemistry is designing drugs with high affinity for their target. The Z-drugs were designed to have high affinity for:

• A. All GABA-A receptor subtypes equally.
• B. The BZD binding site on a specific subset of GABA-A receptors.
• C. The serotonin transporter.
• D. Orexin receptors.

Answer: B. The BZD binding site on a specific subset of GABA-A receptors.

20. The lack of significant muscle relaxant or anticonvulsant activity with Z-drugs is attributed to their lower affinity for which GABA-A receptor alpha subunits?

• A. α1 and α5
• B. α2 and α3
• C. Only the γ subunit
• D. Only the β subunit

Answer: B. α2 and α3

21. The chemical structure of buspirone makes it a substrate for CYP3A4. Co-administration with a potent CYP3A4 inhibitor like ketoconazole would:

• A. Decrease buspirone levels.
• B. Increase buspirone levels, raising the risk of side effects.
• C. Have no effect on buspirone levels.
• D. Increase the absorption of ketoconazole.

Answer: B. Increase buspirone levels, raising the risk of side effects.

22. Suvorexant is a DORA, which stands for:

• A. Dopamine-Orexin Receptor Agonist
• B. Dual Orexin Receptor Antagonist
• C. Direct Opiate Receptor Agonist
• D. Dihydro-Orotate Reductase Antagonist

Answer: B. Dual Orexin Receptor Antagonist

23. The development of non-benzodiazepines like the Z-drugs illustrates the medicinal chemistry principle of:

• A. Increasing a drug’s toxicity.
• B. Designing drugs with no clear mechanism of action.
• C. Seeking receptor subtype selectivity to separate therapeutic effects from side effects.
• D. Making molecules as large as possible.

Answer: C. Seeking receptor subtype selectivity to separate therapeutic effects from side effects.

24. Which of the following non-benzodiazepines would be a poor choice for providing immediate relief from an acute panic attack?

• A. Zolpidem
• B. Eszopiclone
• C. Buspirone
• D. Zaleplon

Answer: C. Buspirone

25. Unlike benzodiazepines, buspirone does not carry a significant risk of physical dependence or withdrawal. This is a direct consequence of its:

• A. Short half-life.
• B. Non-GABAergic mechanism of action.
• C. High cost.
• D. Route of administration.

Answer: B. Non-GABAergic mechanism of action.

26. The term “pharmacophore” refers to the essential structural features of a molecule required for its biological activity. The pharmacophore for Z-drugs must include features that allow it to bind to the:

• A. Melatonin receptor.
• B. Serotonin transporter.
• C. BZD site of the GABA-A receptor.
• D. Orexin receptor.

Answer: C. BZD site of the GABA-A receptor.

27. From a physicochemical standpoint, a key property for any CNS-active drug, including non-benzodiazepines, is the ability to:

• A. Remain ionized at physiological pH.
• B. Cross the blood-brain barrier.
• C. Bind irreversibly to plasma proteins.
• D. Be highly water-soluble.

Answer: B. Cross the blood-brain barrier.

28. The medicinal chemistry of ramelteon focused on creating a stable, orally available molecule that specifically targets:

• A. The brain’s primary inhibitory system.
• B. The brain’s primary wakefulness system.
• C. The brain’s suprachiasmatic nucleus, which controls circadian rhythms.
• D. The brain’s reward system.

Answer: C. The brain’s suprachiasmatic nucleus, which controls circadian rhythms.

29. The introduction of the orexin receptor antagonist class represents a new medicinal chemistry approach to insomnia that differs from all GABAergic and melatonergic agents by:

• A. Promoting sleep via sedation.
• B. Promoting sleep by blocking wake-promoting signals.
• C. Resetting the circadian rhythm.
• D. Inducing muscle relaxation.

Answer: B. Promoting sleep by blocking wake-promoting signals.

30. The knowledge that Z-drugs are structurally different from BZDs but have a similar binding site is a key concept from which unit in the PHA5789C course?

• A. Unit 5.2 Medicinal Chemistry of Benzodiazepines (Anxiolytics & Sleep), Non-Benzodiazepines.
• B. Unit 4.2 Medicinal Chemistry of Antidepressants.
• C. Unit 3.3 Medicinal Chemistry of Antipsychotics.
• D. Unit 2.3 Medicinal Chemistry of Neurodegenerative Diseases.

Answer: A. Unit 5.2 Medicinal Chemistry of Benzodiazepines (Anxiolytics & Sleep), Non-Benzodiazepines.

31. The primary structural difference between zaleplon and zolpidem is that zaleplon is a _________, while zolpidem is an imidazopyridine.

• A. Cyclopyrrolone
• B. Pyrazolopyrimidine
• C. Benzodiazepine
• D. Barbiturate

Answer: B. Pyrazolopyrimidine

32. The term “agonism” in medicinal chemistry and pharmacology refers to a drug’s ability to:

• A. Bind to a receptor and produce a biological response.
• B. Bind to a receptor and block a response.
• C. Bind to an enzyme and inhibit it.
• D. Be metabolized by the liver.

Answer: A. Bind to a receptor and produce a biological response.

33. Buspirone’s delayed onset of action is a critical counseling point derived from its:

• A. Chemical instability.
• B. Pharmacological mechanism requiring neuroadaptation.
• C. Poor oral absorption.
• D. Rapid renal clearance.

Answer: B. Pharmacological mechanism requiring neuroadaptation.

34. The fact that zolpidem has a higher affinity for GABA-A receptors containing the α1 subunit compared to those containing α2 or α3 subunits is an example of:

• A. Receptor subtype selectivity.
• B. Non-specific binding.
• C. Covalent bonding.
• D. Intrinsic activity.

Answer: A. Receptor subtype selectivity.

35. A medicinal chemist aiming to design a new hypnotic with fewer “hangover” effects would focus on creating a molecule with:

• A. A very long half-life.
• B. A short half-life and no active metabolites.
• C. High affinity for all GABA-A receptor subtypes.
• D. Poor CNS penetration.

Answer: B. A short half-life and no active metabolites.

36. The metabolism of buspirone by CYP3A4 is a key medicinal chemistry consideration because:

• A. It guarantees the drug is safe for everyone.
• B. It means grapefruit juice can significantly increase buspirone levels.
• C. It ensures the drug has a rapid onset of action.
• D. It prevents the drug from crossing the blood-brain barrier.

Answer: B. It means grapefruit juice can significantly increase buspirone levels.

37. Which non-benzodiazepine works on a completely different neurotransmitter system than GABA or serotonin for its primary therapeutic effect?

• A. Zolpidem
• B. Buspirone
• C. Suvorexant
• D. Eszopiclone

Answer: C. Suvorexant

38. The development of eszopiclone from zopiclone is an application of which medicinal chemistry principle?

• A. Bioisosterism
• B. Prodrug design
• C. Chiral switching (isolating a single, active enantiomer)
• D. Drug repurposing

Answer: C. Chiral switching (isolating a single, active enantiomer)

39. If a drug is a substrate of P-glycoprotein (a drug efflux pump), what is a potential medicinal chemistry challenge?

• A. The drug will be too water-soluble.
• B. The drug may be actively transported out of the brain, limiting its CNS effects.
• C. The drug will have no side effects.
• D. The drug will not be metabolized.

Answer: B. The drug may be actively transported out of the brain, limiting its CNS effects.

40. The lack of anxiolytic effect from ramelteon is expected based on its chemical structure and mechanism, which has no significant activity at:

• A. Melatonin receptors.
• B. Orexin receptors.
• C. GABA or serotonin systems.
• D. Histamine receptors.

Answer: C. GABA or serotonin systems.

41. The chemical properties of buspirone make it unsuitable for which clinical situation?

• A. Long-term management of GAD.
• B. Augmentation of an SSRI.
• C. PRN (as-needed) use for an acute panic attack.
• D. Use in patients with a history of BZD abuse.

Answer: C. PRN (as-needed) use for an acute panic attack.

42. A key SAR principle for Z-drugs is that their non-BZD scaffolds must still be able to adopt a 3D conformation that mimics what?

• A. The structure of GABA.
• B. The structure of serotonin.
• C. The essential binding features of a classic benzodiazepine.
• D. The structure of melatonin.

Answer: C. The essential binding features of a classic benzodiazepine.

43. A drug’s half-life is a pharmacokinetic property that is directly influenced by its chemical structure’s susceptibility to:

• A. Metabolism and elimination.
• B. Light and heat.
• C. Patient preference.
• D. The placebo effect.

Answer: A. Metabolism and elimination.

44. The main medicinal chemistry reason Z-drugs have largely replaced barbiturates for insomnia is:

• A. Z-drugs are less expensive.
• B. Z-drugs have a wider therapeutic index and lower risk of fatal overdose because they are modulators, not direct agonists, of the GABA-A receptor.
• C. Z-drugs are more potent.
• D. Z-drugs are available over-the-counter.

Answer: B. Z-drugs have a wider therapeutic index and lower risk of fatal overdose because they are modulators, not direct agonists, of the GABA-A receptor.

45. Which non-benzodiazepine has a mechanism that does not involve direct binding to a neurotransmitter or neuropeptide receptor?

• A. Zolpidem (binds to GABA-A)
• B. Buspirone (binds to 5-HT1A)
• C. Ramelteon (binds to MT1/MT2)
• D. This question is misleading; all of these agents bind to receptors.

Answer: D. This question is misleading; all of these agents bind to receptors.

46. The structural diversity of non-benzodiazepines demonstrates that:

• A. Only one chemical structure can produce a specific pharmacological effect.
• B. Different chemical scaffolds can achieve a similar pharmacological effect by interacting with the same biological target.
• C. A drug’s structure is unrelated to its function.
• D. All hypnotics must contain a diazepine ring.

Answer: B. Different chemical scaffolds can achieve a similar pharmacological effect by interacting with the same biological target.

47. The anxiolytic indication for some SNRIs/SSRIs versus the hypnotic indication for Z-drugs, despite some overlapping neurobiology, is a key concept in:

• A. Pharmacy law.
• B. The management of sleep-wake and anxiety disorders.
• C. Drug compounding.
• D. Hospital administration.

Answer: B. The management of sleep-wake and anxiety disorders.

48. Designing a drug to be a partial agonist, like buspirone, is a medicinal chemistry strategy that can:

• A. Produce a maximal effect at all times.
• B. Provide a “ceiling” effect, potentially reducing the risk of overstimulation and some side effects compared to a full agonist.
• C. Guarantee a rapid onset of action.
• D. Ensure the drug is a potent enzyme inhibitor.

Answer: B. Provide a “ceiling” effect, potentially reducing the risk of overstimulation and some side effects compared to a full agonist.

49. A major focus of modern medicinal chemistry for CNS drugs is improving selectivity. This is done to:

• A. Increase the number of side effects.
• B. Reduce off-target binding, which is a primary cause of unwanted side effects.
• C. Make the drugs more difficult to synthesize.
• D. Ensure the drug interacts with every receptor in the brain.

Answer: B. Reduce off-target binding, which is a primary cause of unwanted side effects.

50. An understanding of the medicinal chemistry of non-benzodiazepines allows a pharmacist to:

• A. Predict their clinical effects and side effects based on their mechanism and selectivity.
• B. Anticipate drug-drug interactions based on their metabolic pathways.
• C. Counsel patients on why their medication works differently from other sleep aids or anxiolytics.
• D. All of the above.

Answer: D. All of the above.