MCQ Quiz: Medicinal Chemistry of Drugs Used in Migraine Disorders

The evolution of migraine therapy is a powerful example of successful medicinal chemistry, moving from non-selective compounds to highly targeted agents based on a deeper understanding of the disorder’s pathophysiology. As covered in the Patient Care VII: Brain and Behavior course, the medicinal chemistry of these drugs explains their mechanisms, selectivity, and clinical profiles. This quiz will test your knowledge on the structure-activity relationships of triptans, the chemical nature of CGRP antagonists, and the properties that differentiate the various classes of migraine medications.

1. The chemical structure of the “triptan” class of drugs is based on which core scaffold, making them structurally similar to serotonin?

• A. A phenethylamine scaffold
• B. An indole scaffold
• C. A steroid nucleus
• D. A benzodiazepine ring

Answer: B. An indole scaffold

2. Triptans exert their therapeutic effect by acting as selective agonists at which two serotonin receptor subtypes?

• A. 5-HT2A and 5-HT2C
• B. 5-HT3 and 5-HT4
• C. 5-HT1B and 5-HT1D
• D. 5-HT6 and 5-HT7

Answer: C. 5-HT1B and 5-HT1D

3. From a medicinal chemistry perspective, the development of “second-generation” triptans (e.g., zolmitriptan, rizatriptan) over the first-in-class sumatriptan was aimed at improving which physicochemical property?

• A. Decreased water solubility
• B. Increased lipophilicity for better CNS penetration and oral bioavailability
• C. Decreased potency
• D. A longer, more rigid structure

Answer: B. Increased lipophilicity for better CNS penetration and oral bioavailability

4. The vasoconstrictive effect of triptans, which is part of their mechanism but also a cause for contraindications, is mediated by agonism at which receptor located on cranial blood vessels?

• A. 5-HT1D
• B. 5-HT2A
• C. 5-HT1B
• D. CGRP receptors

Answer: C. 5-HT1B

5. The newer “gepant” class of drugs (e.g., ubrogepant) are classified chemically as:

• A. Large protein monoclonal antibodies
• B. Small molecule CGRP receptor antagonists
• C. Serotonin receptor agonists
• D. Ergot alkaloids

Answer: B. Small molecule CGRP receptor antagonists

6. Monoclonal antibodies used for migraine prophylaxis (e.g., erenumab) are large protein molecules. What is the medicinal chemistry advantage of their structure?

• A. They are orally active and rapidly absorbed.
• B. They have a very short half-life, requiring daily dosing.
• C. They are highly specific for their target (CGRP or its receptor) and have a very long half-life, allowing for infrequent dosing.
• D. They can easily cross the blood-brain barrier.

Answer: C. They are highly specific for their target (CGRP or its receptor) and have a very long half-life, allowing for infrequent dosing.

7. The “Medicinal Chemistry of Drugs Used in Migraine Disorders” is a core lecture in which Patient Care course module?

• A. Module 5: Anxiety and Sleep-Wake Disorders
• B. Module 6: Epilepsy
• C. Module 7: Other Neuropsychiatric Disorders
• D. Module 2: Neurodegenerative Disorders

Answer: C. Module 7: Other Neuropsychiatric Disorders

8. The chemical structure of ergot alkaloids (e.g., ergotamine) is complex and rigid, and it resembles several different neurotransmitters. This lack of selectivity explains its:

• A. Favorable side effect profile.
• B. Broad receptor-binding profile and extensive side effects.
• C. Use as a first-line agent for all migraine patients.
• D. High water solubility.

Answer: B. Broad receptor-binding profile and extensive side effects.

9. The sulfonamide group present on the structure of sumatriptan and other triptans is responsible for which potential issue?

• A. Increased lipophilicity
• B. The potential for hypersensitivity reactions in patients with a sulfa allergy.
• C. A very long half-life
• D. Resistance to metabolism

Answer: B. The potential for hypersensitivity reactions in patients with a sulfa allergy.

10. Lasmiditan is a newer acute migraine medication with a novel chemical mechanism. It is a selective agonist at which receptor?

• A. 5-HT1B
• B. CGRP receptor
• C. 5-HT1F
• D. 5-HT1D

Answer: C. 5-HT1F

11. The advantage of designing a 5-HT1F agonist like lasmiditan is that this receptor is not expressed on vascular smooth muscle, thus avoiding:

• A. The anti-migraine effect.
• B. Vasoconstriction, making it potentially safer for patients with cardiovascular risk factors.
• C. CNS penetration.
• D. Oral bioavailability.

Answer: B. Vasoconstriction, making it potentially safer for patients with cardiovascular risk factors.

12. The term “Structure-Activity Relationship” (SAR) refers to:

• A. The relationship between a drug’s marketing and its clinical use.
• B. How the specific chemical structure of a molecule dictates its biological activity.
• C. The legal classification of a drug.
• D. The cost of synthesizing a drug.

Answer: B. How the specific chemical structure of a molecule dictates its biological activity.

13. A key physicochemical property that medicinal chemists manipulate to improve a drug’s ability to cross the blood-brain barrier is:

• A. Water solubility (hydrophilicity)
• B. Molecular weight
• C. Lipophilicity (LogP)
• D. Acidity (pKa)

Answer: C. Lipophilicity (LogP)

14. Monoclonal antibodies targeting the CGRP pathway are administered via which route, due to their large protein structure?

• A. Oral
• B. Sublingual
• C. Inhalation
• D. Subcutaneous or Intravenous injection

Answer: D. Subcutaneous or Intravenous injection

15. The development of triptans was a classic example of rational drug design that targeted a specific pathophysiological mechanism involving which neurotransmitter?

• A. Dopamine
• B. Serotonin
• C. GABA
• D. Norepinephrine

Answer: B. Serotonin

16. Which of the following is NOT a primary goal when medicinal chemists design new migraine drugs?

• A. Increase selectivity for the target receptor.
• B. Improve the pharmacokinetic profile (e.g., oral bioavailability, half-life).
• C. Reduce off-target side effects.
• D. Increase binding to as many receptors as possible.

Answer: D. Increase binding to as many receptors as possible.

17. The basic amine side chain on the triptan structure is crucial because at physiological pH, it is protonated, allowing it to:

• A. Form a salt bridge or ionic bond with the receptor binding site.
• B. Be rapidly metabolized.
• C. Become highly lipophilic.
• D. Repel the receptor.

Answer: A. Form a salt bridge or ionic bond with the receptor binding site.

18. The “gepants” are small molecules, which gives them what advantage over monoclonal antibodies?

• A. A much longer half-life.
• B. They can be administered orally.
• C. They are more specific for their target.
• D. They never cause side effects.

Answer: B. They can be administered orally.

19. Why can’t a monoclonal antibody be administered orally?

• A. It tastes bad.
• B. As a large protein, it would be degraded by proteases in the gastrointestinal tract and is too large to be absorbed.
• C. It is not stable in tablet form.
• D. It is too expensive to put in a tablet.

Answer: B. As a large protein, it would be degraded by proteases in the gastrointestinal tract and is too large to be absorbed.

20. The “pharmacophore” for the triptan class includes the indole ring and the:

• A. Sulfonamide group.
• B. Protonatable side-chain amine.
• C. Phenyl ring.
• D. C-5 substituent.

Answer: B. Protonatable side-chain amine.

21. The medicinal chemistry of erenumab (Aimovig) is unique among the migraine mAbs because its structure is designed to target:

• A. The CGRP ligand itself.
• B. The CGRP receptor.
• C. The 5-HT1B receptor.
• D. The 5-HT1D receptor.

Answer: B. The CGRP receptor.

22. An understanding of the medicinal chemistry of migraine drugs helps the pharmacist:

• A. Predict and explain differences in onset of action between triptans.
• B. Understand the rationale for contraindications.
• C. Explain the mechanism of action to patients.
• D. All of the above.

Answer: D. All of the above.

23. The metabolism of many triptans involves which enzyme, leading to a potential interaction with MAOIs?

• A. Aldehyde oxidase
• B. Monoamine Oxidase A (MAO-A)
• C. CYP2D6
• D. UGT1A1

Answer: B. Monoamine Oxidase A (MAO-A)

24. The development of CGRP-targeted therapies was a direct result of understanding its role in:

• A. The etiology and pathophysiology of migraine.
• B. The management of epilepsy.
• C. The treatment of anxiety.
• D. The cause of Alzheimer’s disease.

Answer: A. The etiology and pathophysiology of migraine.

25. A key difference between the chemical nature of a “gepant” and a monoclonal antibody is:

• A. Gepants are large proteins, while mAbs are small molecules.
• B. Gepants are small molecules, while mAbs are large proteins.
• C. Both are small molecules.
• D. Both are large proteins.

Answer: B. Gepants are small molecules, while mAbs are large proteins.

26. The term “agonist” means a molecule that:

• A. Binds to a receptor and blocks its function.
• B. Binds to a receptor and activates it, producing a biological response.
• C. Binds to an enzyme and inhibits it.
• D. Does not interact with receptors.

Answer: B. Binds to a receptor and activates it, producing a biological response.

27. The term “antagonist” means a molecule that:

• A. Binds to a receptor and activates it.
• B. Binds to a receptor but does not activate it, thereby blocking the action of an agonist.
• C. Increases the synthesis of a neurotransmitter.
• D. Is a natural hormone.

Answer: B. Binds to a receptor but does not activate it, thereby blocking the action of an agonist.

28. Why do drugs with higher lipophilicity, like zolmitriptan, generally have a faster onset of action than sumatriptan?

• A. They are absorbed more slowly from the gut.
• B. They cross the blood-brain barrier more rapidly to reach their site of action.
• C. They are less potent at the receptor.
• D. They are metabolized more slowly.

Answer: B. They cross the blood-brain barrier more rapidly to reach their site of action.

29. The non-selective receptor binding profile of ergotamine is a direct result of its ________ chemical structure.

• A. simple and flexible
• B. small
• C. complex and rigid
• D. highly water-soluble

Answer: C. complex and rigid

30. The “Follow-up and monitor a care plan” EPA is relevant to migraine therapy because:

• A. The choice of drug is always correct the first time.
• B. The pharmacist must assess the efficacy and tolerability of a chosen agent, which are dictated by its chemical properties.
• C. Migraine is an acute, self-limiting condition that requires no follow-up.
• D. All migraine drugs work the same way.

Answer: B. The pharmacist must assess the efficacy and tolerability of a chosen agent, which are dictated by its chemical properties.

31. From a medicinal chemistry perspective, prophylactic drugs like topiramate or propranolol are not designed to interact with the same acute targets as triptans. Instead, their structures allow them to:

• A. Acutely abort a migraine attack.
• B. Modulate neuronal excitability to prevent the initiation of an attack.
• C. Only work if a migraine is already present.
• D. Act as potent vasoconstrictors.

Answer: B. Modulate neuronal excitability to prevent the initiation of an attack.

32. The development of different dosage forms for sumatriptan (oral, nasal spray, injection) is a pharmaceutical/medicinal chemistry strategy to:

• A. Increase side effects.
• B. Modify the rate of absorption and onset of action.
• C. Make the drug less effective.
• D. Increase the cost for no reason.

Answer: B. Modify the rate of absorption and onset of action.

33. The chemical stability of a drug is a key consideration in its formulation. Triptans are generally stable as:

• A. Amine salts in solid dosage forms.
• B. Unstable oils.
• C. Gaseous forms.
• D. Reactive aldehydes.

Answer: A. Amine salts in solid dosage forms.

34. The concept of a “pharmacophore” is the minimal structural requirement for a drug to have activity. For triptans, this includes the indole ring and:

• A. A C-5 substituent.
• B. The sulfonamide group.
• C. The basic side-chain nitrogen.
• D. A halogen atom.

Answer: C. The basic side-chain nitrogen.

35. A “prodrug” is an inactive molecule that is converted to an active drug in the body. While not common for triptans, this is a medicinal chemistry strategy used to:

• A. Decrease bioavailability.
• B. Improve absorption or distribution.
• C. Increase side effects.
• D. Make a drug less stable.

Answer: B. Improve absorption or distribution.

36. The medicinal chemistry of NSAIDs, sometimes used for mild migraine, involves a structure that allows them to inhibit which enzyme?

• A. Monoamine oxidase
• B. CGRP synthase
• C. Cyclooxygenase (COX)
• D. Acetylcholinesterase

Answer: C. Cyclooxygenase (COX)

37. The charge state of a drug, which is determined by its pKa and the pH of the environment, is a key medicinal chemistry concept because:

• A. It does not affect the drug’s properties.
• B. The ionized form of a drug is typically more water-soluble, while the unionized form crosses biological membranes more easily.
• C. All drugs are neutral at all pH values.
• D. The ionized form of a drug is more lipophilic.

Answer: B. The ionized form of a drug is typically more water-soluble, while the unionized form crosses biological membranes more easily.

38. The side effect of “triptan sensations” (e.g., chest tightness) is thought to be a result of the drug’s agonist activity at which receptors?

• A. Only 5-HT1D receptors in the brain.
• B. 5-HT1B receptors located on blood vessels outside of the brain, like the coronary arteries.
• C. CGRP receptors.
• D. Dopamine receptors.

Answer: B. 5-HT1B receptors located on blood vessels outside of the brain, like the coronary arteries.

39. The success of CGRP-targeted therapies validates the CGRP receptor as a key __________ in migraine pathophysiology.

• A. off-target
• B. drug target
• C. metabolic enzyme
• D. transport protein

Answer: B. drug target

40. Why is medicinal chemistry a foundational science for pharmacy?

• A. It is not.
• B. Because it provides the fundamental link between a drug’s chemical structure and its ultimate effect in a patient.
• C. It is only useful for organic chemists.
• D. It only deals with drug manufacturing.

Answer: B. Because it provides the fundamental link between a drug’s chemical structure and its ultimate effect in a patient.

41. The development of different triptans with varying pharmacokinetic profiles (e.g., half-life) allows for:

• A. The use of the same drug for every patient.
• B. The individualization of therapy based on patient needs (e.g., a longer half-life for a patient with migraine recurrence).
• C. More complicated dosing regimens.
• D. Higher rates of medication-overuse headache.

Answer: B. The individualization of therapy based on patient needs (e.g., a longer half-life for a patient with migraine recurrence).

42. The high specificity of monoclonal antibodies is a direct result of their:

• A. Small molecular size.
• B. Unique protein structure, which allows them to bind to a single, specific epitope on their target.
• C. Oral bioavailability.
• D. Rapid metabolism.

Answer: B. Unique protein structure, which allows them to bind to a single, specific epitope on their target.

43. A key medicinal chemistry challenge in designing oral CGRP monoclonal antibodies is:

• A. This is not possible, as antibodies are large proteins that cannot be taken orally.
• B. Finding a stable salt form.
• C. Ensuring they taste good.
• D. Making them small enough to fit in a capsule.

Answer: A. This is not possible, as antibodies are large proteins that cannot be taken orally.

44. The “ditans” (e.g., lasmiditan) represent a new chemical class designed to be more selective than triptans by avoiding activity at which receptor?

• A. 5-HT1D
• B. 5-HT1F
• C. 5-HT1B
• D. CGRP receptor

Answer: C. 5-HT1B

45. Which of the following best describes the relationship between the structures of serotonin and sumatriptan?

• A. They are identical.
• B. They are completely unrelated.
• C. Sumatriptan contains an indole ring, making it a structural analogue of serotonin.
• D. Serotonin is a prodrug of sumatriptan.

Answer: C. Sumatriptan contains an indole ring, making it a structural analogue of serotonin.

46. The medicinal chemistry of antiemetics used for migraine-associated nausea, like prochlorperazine, involves antagonism at which receptor?

• A. Serotonin 5-HT1D
• B. Dopamine D2
• C. CGRP
• D. Muscarinic M1

Answer: B. Dopamine D2

47. The ability of a drug to exist in different spatial arrangements, known as stereoisomers, is a key concept in medicinal chemistry because:

• A. It has no impact on pharmacology.
• B. Different isomers can have vastly different activities and side effect profiles.
• C. All drugs are achiral.
• D. Only one isomer can be synthesized.

Answer: B. Different isomers can have vastly different activities and side effect profiles.

48. Why is it important for a pharmacist to understand the chemical class of a migraine drug (e.g., triptan, gepant, ditan)?

• A. It is not important.
• B. To predict its mechanism of action, potential side effects, and contraindications.
• C. To calculate the price.
• D. To determine the color of the tablet.

Answer: B. To predict its mechanism of action, potential side effects, and contraindications.

49. The development of a drug that can both treat an acute migraine and prevent future attacks, like rimegepant, is a significant advance in migraine:

• A. Pathophysiology
• B. Medicinal chemistry and pharmacology
• C. Diagnostics
• D. Surgery

Answer: B. Medicinal chemistry and pharmacology

50. The story of migraine drug development, from non-selective ergots to highly targeted mAbs, is a primary example of:

• A. Serendipity in drug discovery.
• B. The failure of medicinal chemistry.
• C. Rational drug design based on an understanding of pathophysiology.
• D. The process of generic drug manufacturing.

Answer: C. Rational drug design based on an understanding of pathophysiology.