MCQ Quiz: Medicinal Chemistry of Antidepressants

Welcome, pharmacy students! This MCQ quiz is tailored to sharpen your understanding of the medicinal chemistry of antidepressants, a cornerstone of psychopharmacology. We will explore the fascinating relationship between the chemical structure of these drugs and their therapeutic effects. This quiz covers the key structural features, structure-activity relationships (SAR), and how molecular design influences the efficacy and side effect profiles of major classes like TCAs, SSRIs, SNRIs, and MAOIs. A solid grasp of medicinal chemistry is essential for a pharmacist to truly understand drug action, interactions, and patient counseling

1. The classic tricyclic antidepressant (TCA) structure consists of a three-ring nucleus. The nature of the amine on the side chain determines its initial selectivity. Tertiary amines, like imipramine, are generally less selective and inhibit the reuptake of:

• A. Serotonin only
• B. Norepinephrine only
• C. Both serotonin and norepinephrine
• D. Dopamine only

Answer: C. Both serotonin and norepinephrine

2. The active metabolite of imipramine is desipramine. What structural change occurs during metabolism and how does it affect its selectivity?

• A. Addition of a methyl group, making it more serotonin-selective.
• B. Removal of a methyl group (N-demethylation) to form a secondary amine, making it more norepinephrine-selective.
• C. Hydroxylation of the tricyclic ring, making it inactive.
• D. Glucuronidation of the amine, making it more dopamine-selective.

Answer: B. Removal of a methyl group (N-demethylation) to form a secondary amine, making it more norepinephrine-selective.

3. The significant anticholinergic side effects (dry mouth, constipation) of TCAs like amitriptyline are due to their structural ability to bind to which unintended receptor?

• A. Histamine H1 receptors
• B. Alpha-1 adrenergic receptors
• C. Muscarinic M1 acetylcholine receptors
• D. Dopamine D2 receptors

Answer: C. Muscarinic M1 acetylcholine receptors

4. What structural feature on fluoxetine (Prozac) is critical for its potency and selectivity as a Selective Serotonin Reuptake Inhibitor (SSRI)?

• A. A methoxy group on the phenoxy ring
• B. A trifluoromethyl (-CF3) group on the phenoxy ring
• C. A flat, rigid tricyclic system
• D. A primary amine on the side chain

Answer: B. A trifluoromethyl (-CF3) group on the phenoxy ring

5. Sertraline (Zoloft) contains a dichlorophenyl group attached to a tetrahydronaphthalene ring system. What is the medicinal chemistry advantage of this structure?

• A. It makes the drug a potent MAO inhibitor.
• B. It provides a more flexible structure than TCAs, leading to high selectivity for the serotonin transporter (SERT).
• C. It causes significant histamine H1 receptor blockade.
• D. It ensures the drug is rapidly metabolized and cleared.

Answer: B. It provides a more flexible structure than TCAs, leading to high selectivity for the serotonin transporter (SERT).

6. Escitalopram is the S-enantiomer of citalopram. From a medicinal chemistry perspective, why is escitalopram considered more effective than the racemic mixture?

• A. The R-enantiomer is responsible for all the side effects.
• B. The R-enantiomer can interfere with the binding of the active S-enantiomer to the serotonin transporter.
• C. The S-enantiomer has a much longer half-life.
• D. The S-enantiomer also blocks dopamine reuptake.

Answer: B. The R-enantiomer can interfere with the binding of the active S-enantiomer to the serotonin transporter.

7. The general structure of many SSRIs, such as fluoxetine and paroxetine, is based on which chemical scaffold?

• A. Dibenzazepine
• B. Phenothiazine
• C. Phenoxyphenylalkylamine
• D. Hydrazine

Answer: C. Phenoxyphenylalkylamine

8. The improved side effect profile of SSRIs compared to TCAs is primarily because their chemical structures lack significant affinity for which receptors?

• A. Serotonin 5-HT2A receptors
• B. Muscarinic, histaminic, and alpha-1 adrenergic receptors
• C. Dopamine D2 and D3 receptors
• D. NMDA and GABA receptors

Answer: B. Muscarinic, histaminic, and alpha-1 adrenergic receptors

9. Venlafaxine, an SNRI, is based on a phenethylamine skeleton. Its reuptake inhibition profile is dose-dependent. At lower doses, it primarily inhibits the reuptake of:

• A. Norepinephrine
• B. Dopamine
• C. Both serotonin and norepinephrine equally
• D. Serotonin

Answer: D. Serotonin

10. Duloxetine (Cymbalta) has a naphthyloxy-thiophenepropanamine structure. How does its reuptake inhibition profile differ from venlafaxine?

• A. It is a selective inhibitor of norepinephrine only.
• B. It potently and more balancedly inhibits both SERT and NET across its dose range.
• C. It requires high doses to achieve any norepinephrine reuptake inhibition.
• D. It primarily works by inhibiting dopamine reuptake.

Answer: B. It potently and more balancedly inhibits both SERT and NET across its dose range.

11. The older, non-selective MAOIs like phenelzine are often hydrazine derivatives. This hydrazine moiety (-NH-NH2) allows the drug to:

• A. Reversibly bind to the MAO-A isoform only.
• B. Form a stable, covalent bond with the MAO enzyme, leading to irreversible inhibition.
• C. Act as a selective serotonin reuptake inhibitor.
• D. Be rapidly metabolized by CYP2D6.

Answer: B. Form a stable, covalent bond with the MAO enzyme, leading to irreversible inhibition.

12. The dangerous “cheese reaction” associated with irreversible MAOIs is a direct consequence of their medicinal chemistry. It occurs because the inhibition of MAO-A in the gut prevents the metabolism of what dietary substance?

• A. Tryptophan
• B. Phenylalanine
• C. Tyramine
• D. Leucine

Answer: C. Tyramine

13. How does the chemical structure of a reversible inhibitor of MAO-A (RIMA), like moclobemide, lead to a lower risk of the “cheese reaction”?

• A. It only inhibits MAO-B.
• B. It forms a permanent covalent bond with the enzyme.
• C. It can be displaced from the MAO-A enzyme by high concentrations of tyramine, allowing tyramine to be metabolized.
• D. It completely blocks the absorption of tyramine from the GI tract.

Answer: C. It can be displaced from the MAO-A enzyme by high concentrations of tyramine, allowing tyramine to be metabolized.

14. Bupropion is an atypical antidepressant. Its aminoketone structure is chemically related to phenethylamines and is responsible for its unique mechanism of action, which is:

• A. Inhibition of serotonin reuptake.
• B. Inhibition of norepinephrine and dopamine reuptake.
• C. Inhibition of MAO.
• D. Antagonism of histamine receptors.

Answer: B. Inhibition of norepinephrine and dopamine reuptake.

15. Mirtazapine’s tetracyclic chemical structure allows it to act as an antagonist at which key presynaptic autoreceptor, leading to increased release of both serotonin and norepinephrine?

• A. Dopamine D2 autoreceptors
• B. Serotonin 5-HT1A autoreceptors
• C. Alpha-2 adrenergic autoreceptors
• D. Muscarinic M2 autoreceptors

Answer: C. Alpha-2 adrenergic autoreceptors

16. The sedative effects of mirtazapine and TCAs are primarily caused by the ability of their chemical structures to antagonize which receptor?

• A. Serotonin 5-HT3 receptor
• B. Histamine H1 receptor
• C. Alpha-2 adrenergic receptor
• D. Dopamine D1 receptor

Answer: B. Histamine H1 receptor

17. The protonatable amine group found on the side chain of TCAs, SSRIs, and SNRIs is essential for their medicinal activity because it:

• A. Makes the molecule highly lipophilic.
• B. Is responsible for the anticholinergic side effects.
• C. Forms an ionic bond with an acidic residue (like aspartate) in the neurotransmitter transporter binding site.
• D. Undergoes rapid glucuronidation, leading to a short half-life.

Answer: C. Forms an ionic bond with an acidic residue (like aspartate) in the neurotransmitter transporter binding site.

18. From a medicinal chemistry standpoint, the evolution from TCAs to SSRIs represents a shift from a rigid, non-selective scaffold to:

• A. Another equally rigid and non-selective scaffold.
• B. More flexible structures designed with specific substitutions to increase target selectivity.
• C. Larger molecules that cannot cross the blood-brain barrier.
• D. Prodrugs that are activated in the CNS.

Answer: B. More flexible structures designed with specific substitutions to increase target selectivity.

19. Tranylcypromine (Parnate) is a non-hydrazine MAOI. Its structure, which incorporates a cyclopropylamine moiety, still leads to irreversible inhibition. This demonstrates that:

• A. Only hydrazine derivatives can be irreversible inhibitors.
• B. The key to irreversible inhibition is the formation of a highly reactive intermediate that bonds covalently to the enzyme.
• C. All non-hydrazine MAOIs are reversible.
• D. Tranylcypromine is a selective MAO-B inhibitor.

Answer: B. The key to irreversible inhibition is the formation of a highly reactive intermediate that bonds covalently to the enzyme.

20. The structure of Trazodone contains a triazolopyridine ring system. Its primary antidepressant effect is believed to come from its action as a:

• A. Potent serotonin and norepinephrine reuptake inhibitor.
• B. Serotonin 5-HT2A receptor antagonist and weak serotonin reuptake inhibitor.
• C. Irreversible MAO inhibitor.
• D. Dopamine D2 receptor agonist.

Answer: B. Serotonin 5-HT2A receptor antagonist and weak serotonin reuptake inhibitor.

21. In drug design, a “prodrug” is an inactive compound that is metabolized into an active drug. Which of the following antidepressants is considered a prodrug?

• A. Fluoxetine
• B. Sertraline
• C. Lisdexamfetamine (used for ADHD, but conceptually relevant)
• D. None of the common antidepressants are classic prodrugs, but some rely on active metabolites.

Answer: D. None of the common antidepressants are classic prodrugs, but some rely on active metabolites.

22. The logP (lipophilicity) of an antidepressant molecule is a key physicochemical property that influences its ability to:

• A. Dissolve in water.
• B. Cross the blood-brain barrier to reach its target in the CNS.
• C. Bind to plasma proteins.
• D. Both B and C.

Answer: D. Both B and C.

23. The chemical difference between citalopram and escitalopram is that they are:

• A. Prodrug and active drug.
• B. Geometric isomers.
• C. Enantiomers (a type of stereoisomer).
• D. An acid and a base.

Answer: C. Enantiomers (a type of stereoisomer).

24. The noradrenergic effects of SNRIs, such as potential increases in blood pressure, are due to the drug molecule’s ability to bind to and inhibit the:

• A. Serotonin transporter (SERT).
• B. Norepinephrine transporter (NET).
• C. Dopamine transporter (DAT).
• D. Histamine H1 receptor.

Answer: B. Norepinephrine transporter (NET).

25. Vilazodone (Viibryd) has a dual mechanism of action based on its chemical structure. It acts as an SSRI and also as a:

• A. Serotonin 5-HT1A receptor partial agonist.
• B. Dopamine D2 receptor antagonist.
• C. Muscarinic M1 receptor antagonist.
• D. Reversible MAO-A inhibitor.

Answer: A. Serotonin 5-HT1A receptor partial agonist.

26. The development of TCAs was a result of modifying the chemical structure of which class of drugs, originally being investigated for antipsychotic properties?

• A. Barbiturates
• B. Benzodiazepines
• C. Phenothiazines
• D. Opioids

Answer: C. Phenothiazines

27. What is the importance of the skewed (non-planar) conformation of the TCA tricyclic ring system?

• A. It makes the molecule completely flat.
• B. It is essential for fitting into the binding pocket of SERT and NET.
• C. It is responsible for the drug’s poor oral absorption.
• D. It allows the drug to be excreted unchanged by the kidneys.

Answer: B. It is essential for fitting into the binding pocket of SERT and NET.

28. Which functional group is essential for the activity of all non-MAOI antidepressants that work via reuptake inhibition?

• A. A carboxylic acid
• B. An alcohol
• A protonatable amine
• D. An aldehyde

Answer: C. A protonatable amine

29. The metabolism of many antidepressants, like fluoxetine and paroxetine, involves the CYP2D6 enzyme. From a medicinal chemistry perspective, this means that co-administering a potent CYP2D6 inhibitor could lead to:

• A. Decreased levels of the antidepressant and therapeutic failure.
• B. Increased levels of the antidepressant and potential toxicity.
• C. No change in the antidepressant’s effects.
• D. A switch in the drug’s mechanism of action.

Answer: B. Increased levels of the antidepressant and potential toxicity.

30. The chemical structure of bupropion makes it a poor substrate for SERT, which is why it typically does not cause:

• A. Dry mouth.
• B. Insomnia.
• C. The sexual side effects commonly seen with SSRIs.
• D. Seizures at high doses.

Answer: C. The sexual side effects commonly seen with SSRIs.

31. Vortioxetine (Trintellix) is described as a “multimodal” antidepressant. Its chemical structure allows it to act as an SSRI and also interact with which other targets?

• A. It is a partial agonist/antagonist at several other serotonin receptor subtypes.
• B. It is a potent inhibitor of MAO-A.
• C. It blocks voltage-gated calcium channels.
• D. It antagonizes histamine and muscarinic receptors.

Answer: A. It is a partial agonist/antagonist at several other serotonin receptor subtypes.

32. The term “Structure-Activity Relationship” (SAR) in medicinal chemistry refers to:

• A. The relationship between a drug’s marketing and its sales.
• B. The idea that a drug’s three-dimensional structure is unrelated to its biological effect.
• C. The process of identifying how specific functional groups and the overall structure of a molecule contribute to its pharmacological activity.
• D. A legal agreement between pharmaceutical companies.

Answer: C. The process of identifying how specific functional groups and the overall structure of a molecule contribute to its pharmacological activity.

33. The addition of halogen atoms (like -Cl or -F) to the aromatic rings of SSRIs often serves to:

• A. Decrease the molecule’s lipophilicity.
• B. Increase the molecule’s selectivity and potency for the serotonin transporter.
• C. Make the molecule taste better.
• D. Increase its affinity for histamine receptors.

Answer: B. Increase the molecule’s selectivity and potency for the serotonin transporter.

34. The major structural difference between the SNRI venlafaxine and its active metabolite desvenlafaxine is:

• A. The presence of a cyclopropyl ring.
• B. The N-demethylation of the amine.
• C. The O-demethylation of the cyclohexanol moiety.
• D. The addition of a fluorine atom.

Answer: C. The O-demethylation of the cyclohexanol moiety.

35. A “pharmacophore” is a concept in medicinal chemistry that describes:

• A. The specific dosage form of a drug.
• B. The collection of steric and electronic features necessary for a molecule to interact with a specific biological target.
• C. The patent information for a drug.
• D. The route of drug metabolism.

Answer: B. The collection of steric and electronic features necessary for a molecule to interact with a specific biological target.

36. The relatively high pKa of the side chain amine in most reuptake inhibitors ensures that at physiological pH (7.4), the amine is predominantly in which form?

• A. Un-ionized and neutral.
• B. Ionized and positively charged (protonated).
• C. Ionized and negatively charged (deprotonated).
• D. In a gaseous state.

Answer: B. Ionized and positively charged (protonated).

37. Which TCA is an example of a secondary amine and is known for being more selective for norepinephrine reuptake inhibition?

• A. Amitriptyline
• B. Imipramine
• C. Doxepin
• D. Nortriptyline

Answer: D. Nortriptyline

38. The weight gain associated with TCAs and mirtazapine is linked to their structural ability to block which receptor?

• A. Serotonin 5-HT2C and Histamine H1 receptors
• B. Dopamine D2 receptors
• C. Beta-2 adrenergic receptors
• D. Nicotinic acetylcholine receptors

Answer: A. Serotonin 5-HT2C and Histamine H1 receptors

39. The medicinal chemistry goal of creating SNRIs was to achieve the dual action of TCAs while minimizing side effects by:

• A. Adding a fourth ring to the structure.
• B. Designing molecules with low affinity for muscarinic, histaminic, and alpha-adrenergic receptors.
• C. Making the molecules much larger so they cannot be metabolized.
• D. Ensuring they only inhibit MAO-B.

Answer: B. Designing molecules with low affinity for muscarinic, histaminic, and alpha-adrenergic receptors.

40. Why is a deep understanding of medicinal chemistry important for a practicing pharmacist?

• A. It allows them to synthesize antidepressants in the pharmacy.
• B. It is not important for a practicing pharmacist.
• C. It provides the basis for understanding drug mechanisms, predicting side effects, and anticipating drug-drug interactions based on structure and metabolism.
• D. It is only necessary for passing the licensure exam.

Answer: C. It provides the basis for understanding drug mechanisms, predicting side effects, and anticipating drug-drug interactions based on structure and metabolism.

41. The chemical logic behind a washout period when switching from an irreversible MAOI to an SSRI is based on:

• A. The time it takes for the MAOI to be cleared from the plasma.
• B. The time required for the body to synthesize new MAO enzyme.
• C. The time it takes for the SSRI to reach steady-state concentration.
• D. The need to allow kidney function to recover.

Answer: B. The time required for the body to synthesize new MAO enzyme.

42. Which of the following is NOT a common strategy in medicinal chemistry to improve a drug’s properties?

• A. Modifying functional groups to enhance target binding (SAR).
• B. Altering lipophilicity to improve CNS penetration.
• C. Creating a prodrug to improve oral bioavailability.
• D. Making the molecule as non-selective as possible to hit more targets.

Answer: D. Making the molecule as non-selective as possible to hit more targets.

43. The design of selegiline as a transdermal patch for depression was a medicinal chemistry strategy to:

• A. Increase its affinity for muscarinic receptors.
• B. Partially bypass first-pass metabolism and MAO inhibition in the gut, reducing the risk of the tyramine reaction.
• C. Make the drug more sedating.
• D. Convert it from an MAO-B inhibitor to an MAO-A inhibitor.

Answer: B. Partially bypass first-pass metabolism and MAO inhibition in the gut, reducing the risk of the tyramine reaction.

44. A molecule’s chirality (the presence of a stereocenter) is a critical concept in medicinal chemistry because:

• A. Both enantiomers of a drug always have identical pharmacological activity and side effects.
• B. Biological systems (like receptors and enzymes) are chiral and may interact differently with each enantiomer of a drug.
• C. Chiral drugs are always more potent than achiral drugs.
• D. Chirality only affects a drug’s color and taste.

Answer: B. Biological systems (like receptors and enzymes) are chiral and may interact differently with each enantiomer of a drug.

45. What structural feature of TCAs is primarily responsible for the risk of cardiotoxicity in overdose?

• A. The terminal amine group.
• B. Their ability to block cardiac sodium channels.
• C. Their affinity for histamine receptors.
• D. Their metabolism by CYP3A4.

Answer: B. Their ability to block cardiac sodium channels.

46. Which of the following statements best describes the structure-activity relationship for the side chain of TCAs?

• A. A two-carbon chain is optimal for antidepressant activity.
• B. A three-carbon chain between the ring system and the terminal amine is optimal for activity.
• C. The length of the side chain has no impact on activity.
• D. A four-carbon chain is required for norepinephrine selectivity.

Answer: B. A three-carbon chain between the ring system and the terminal amine is optimal for activity.

47. The chemical properties of bupropion (an aminoketone) make it an inhibitor of which CYP450 enzyme, leading to potential interactions with other drugs?

• A. CYP1A2
• B. CYP3A4
• C. CYP2D6
• D. CYP2C9

Answer: C. CYP2D6

48. Why are drugs with high lipophilicity (like many antidepressants) more likely to have a longer half-life?

• A. They are rapidly excreted by the kidneys.
• B. They are less likely to bind to plasma proteins.
• C. They distribute more extensively into tissues, creating a reservoir that slowly re-enters circulation.
• D. They are not metabolized by the liver.

Answer: C. They distribute more extensively into tissues, creating a reservoir that slowly re-enters circulation.

49. The development of vilazodone and vortioxetine reflects a medicinal chemistry strategy aimed at:

• A. Creating drugs that only block norepinephrine reuptake.
• B. Designing molecules that not only inhibit SERT but also modulate other serotonin receptor subtypes to potentially improve efficacy or tolerability.
• C. Finding new irreversible MAOIs.
• D. Developing antidepressants that work by blocking dopamine receptors.

Answer: B. Designing molecules that not only inhibit SERT but also modulate other serotonin receptor subtypes to potentially improve efficacy or tolerability.

50. The “privileged structure” concept in medicinal chemistry refers to a chemical scaffold that can bind to multiple, often related, biological targets. Which class of antidepressants best exemplifies a privileged structure with broad receptor activity?

• A. SSRIs
• B. MAOIs
• C. TCAs
• D. SNRIs

Answer: C. TCAs