MCQ Quiz: Medicinal Chemistry of Addiction Treatment Including Ethanol

The development of effective treatments for Substance Use Disorders (SUDs) is a triumph of medicinal chemistry. By understanding the precise chemical structures, functional groups, and physicochemical properties of drugs, scientists can design molecules that interact with specific neurobiological targets to combat addiction. For PharmD students, studying the medicinal chemistry of these agents—from the sulfur atoms in disulfiram to the complex scaffold of buprenorphine—provides a deep, foundational understanding of their mechanisms of action, structure-activity relationships, and metabolic pathways. This quiz, drawing on concepts from the Patient Care VII and Principles of Medicinal Chemistry curricula, will test your knowledge of the chemical principles underlying the pharmacotherapy of alcohol, opioid, and tobacco use disorders.

1. The primary metabolic pathway for ethanol involves its oxidation to acetaldehyde by alcohol dehydrogenase (ADH), followed by oxidation to acetate by what enzyme?

• a) Cytochrome P450 2E1 (CYP2E1)
• b) Aldehyde dehydrogenase (ALDH)
• c) Catalase
• d) Monoamine oxidase (MAO) Answer: b) Aldehyde dehydrogenase (ALDH)

2. Disulfiram exerts its therapeutic effect as an aversive agent for alcohol use disorder by irreversibly inhibiting which enzyme?

• a) Alcohol dehydrogenase (ADH)
• b) Aldehyde dehydrogenase (ALDH)
• c) CYP2E1
• d) Dopamine beta-hydroxylase Answer: b) Aldehyde dehydrogenase (ALDH)

3. The structure of disulfiram, a dithiocarbamate, contains which key element that is crucial for its covalent modification and inactivation of ALDH?

• a) Nitrogen
• b) Oxygen
• c) Sulfur
• d) Fluorine Answer: c) Sulfur

4. Naltrexone, an opioid antagonist used for both Alcohol Use Disorder and Opioid Use Disorder, has a core structure based on which chemical scaffold?

• a) Phenylpiperidine
• b) Benzodiazepine
• c) Morphinan
• d) Barbiturate Answer: c) Morphinan

5. What structural modification on the nitrogen atom of the morphinan ring system typically converts a mu-opioid agonist (like morphine) into an antagonist (like naloxone or naltrexone)?

• a) Replacing the N-methyl group with a larger substituent like N-allyl or N-cyclopropylmethyl.
• b) Removing the nitrogen atom completely.
• c) Adding a second methyl group to the nitrogen.
• d) Converting the tertiary amine to a quaternary ammonium salt. Answer: a) Replacing the N-methyl group with a larger substituent like N-allyl or N-cyclopropylmethyl.

6. Acamprosate (Campral) is a structural analogue of which endogenous amino acid, helping to explain its proposed mechanism of modulating GABA and glutamate systems?

• a) Glycine
• b) Taurine
• c) Glutamate
• d) Aspartate Answer: b) Taurine

7. From a physicochemical standpoint, acamprosate is a highly polar, zwitterionic molecule. How does this property affect its oral bioavailability?

• a) It results in very high oral bioavailability.
• b) It results in very poor oral bioavailability.
• c) It has no effect on oral bioavailability.
• d) It allows for rapid penetration of the blood-brain barrier. Answer: b) It results in very poor oral bioavailability.

8. Varenicline (Chantix) was designed as a rigid analogue of what endogenous ligand to achieve its partial agonist activity at nicotinic acetylcholine receptors?

• a) Dopamine
• b) Serotonin
• c) Acetylcholine
• d) Nicotine Answer: d) Nicotine

9. Buprenorphine’s complex structure, derived from thebaine, includes a bulky N-cyclopropylmethyl group and a C7 side chain. These features contribute to its unique pharmacology as a:

• a) Full mu-opioid agonist
• b) Pure mu-opioid antagonist
• c) Partial mu-opioid agonist
• d) Selective serotonin reuptake inhibitor Answer: c) Partial mu-opioid agonist

10. Methadone is an acyclic, synthetic opioid agonist. Its clinical efficacy is primarily attributed to which enantiomer?

• a) The (S)-(+)-enantiomer
• b) The (R)-(-)-enantiomer
• c) The racemic mixture is required for activity
• d) Both enantiomers are inactive but their metabolite is active Answer: b) The (R)-(-)-enantiomer

11. The conversion of heroin (diacetylmorphine) to morphine in the brain is an example of what medicinal chemistry concept?

• a) A soft drug that is rapidly inactivated.
• b) A prodrug that is metabolized to a more active compound.
• c) An isomer that racemizes in vivo.
• d) A drug that inhibits its own metabolism. Answer: b) A prodrug that is metabolized to a more active compound.

12. The increased lipophilicity of heroin compared to morphine, due to the two acetyl groups, allows it to:

• a) Be more easily excreted by the kidneys.
• b) Have a lower affinity for the mu-opioid receptor.
• c) Cross the blood-brain barrier more rapidly and in greater concentrations.
• d) Be resistant to metabolism by liver enzymes. Answer: c) Cross the blood-brain barrier more rapidly and in greater concentrations.

13. Bupropion, used for smoking cessation, is chemically classified as an:

• a) Aminoketone antidepressant
• b) Opiate alkaloid
• c) Nicotine analogue
• d) Benzodiazepine Answer: a) Aminoketone antidepressant

14. The addition of the hydrophilic glucuronide moiety to morphine during Phase II metabolism results in a compound that is:

• a) More lipid-soluble and harder to excrete.
• b) More water-soluble and more easily excreted renally.
• c) More potent at the mu-opioid receptor.
• d) A CPY2D6 inhibitor. Answer: b) More water-soluble and more easily excreted renally.

15. The structure of benzodiazepines features a fusion of a benzene ring and which seven-membered heterocyclic ring?

• a) A pyridine ring
• b) A diazepine ring
• c) A thiazole ring
• d) A piperidine ring Answer: b) A diazepine ring

16. From a structure-activity relationship (SAR) perspective, what is the role of the electronegative group at the C7 position of the benzodiazepine scaffold?

• a) It decreases the duration of action.
• b) It is essential for anxiolytic activity.
• c) It makes the molecule less potent.
• d) It is the primary site of metabolism. Answer: b) It is essential for anxiolytic activity.

17. The primary structural difference between naloxone and naltrexone is the N-substituent, which is an allyl group in naloxone and a ________ group in naltrexone.

• a) Methyl
• b) Ethyl
• c) Cyclopropylmethyl
• d) Propyl Answer: c) Cyclopropylmethyl

18. This structural difference between naloxone and naltrexone primarily affects their:

• a) Mechanism of action
• b) Oral bioavailability and duration of action
• c) Receptor binding affinity
• d) Water solubility Answer: b) Oral bioavailability and duration of action

19. Cocaine, a stimulant, is chemically classified as a tropane alkaloid. Its reinforcing effects are due to its ability to block the reuptake of which neurotransmitters?

• a) Acetylcholine and GABA
• b) Dopamine, norepinephrine, and serotonin
• c) Only histamine
• d) Glycine and glutamate Answer: b) Dopamine, norepinephrine, and serotonin

20. The metabolism of cocaine by plasma and liver esterases produces which major, inactive metabolite that is often tested for in urine drug screens?

• a) Norcocaine
• b) Cocaethylene
• c) Benzoylecgonine
• d) Ecgonine Answer: c) Benzoylecgonine

21. When cocaine and ethanol are used concurrently, a unique active metabolite is formed via transesterification in the liver. What is this metabolite called?

• a) Norcocaine
• b) Cocaethylene
• c) Benzoylecgonine
• d) Ecgonine Answer: b) Cocaethylene

22. Amphetamine’s structure is based on which simple chemical backbone?

• a) Phenanthrene
• b) Phenylethylamine
• c) Indole
• d) Pyridine Answer: b) Phenylethylamine

23. The presence of a methyl group on the alpha-carbon of the amphetamine structure makes it more resistant to degradation by which enzyme compared to dopamine?

• a) Aldehyde dehydrogenase (ALDH)
• b) Monoamine oxidase (MAO)
• c) Catechol-O-methyltransferase (COMT)
• d) CYP3A4 Answer: b) Monoamine oxidase (MAO)

24. From a medicinal chemistry standpoint, a drug’s ability to exist in an ionized or non-ionized state at physiological pH, governed by its pKa, is critical for:

• a) Its color
• b) Its ability to cross cell membranes and the blood-brain barrier.
• c) Its manufacturing cost.
• d) Its patent life. Answer: b) Its ability to cross cell membranes and the blood-brain barrier.

25. Why is the 6-hydroxyl group on the morphinan scaffold of opioids important for activity?

• a) It is a key hydrogen bond donor/acceptor for receptor interaction.
• b) It makes the molecule completely water-insoluble.
• c) It confers antagonist properties.
• d) It prevents metabolism by the liver. Answer: a) It is a key hydrogen bond donor/acceptor for receptor interaction.

26. The high potency of fentanyl and its analogues is attributed in part to their:

• a) High lipophilicity, allowing rapid CNS penetration.
• b) Zwitterionic properties at physiological pH.
• c) Inability to be metabolized by CYP enzymes.
• d) Structural similarity to benzodiazepines. Answer: a) High lipophilicity, allowing rapid CNS penetration.

27. The acidic nature of barbiturates is due to the lactam-lactim tautomerism involving which functional group?

• a) A carboxylic acid
• b) A phenol
• c) An imide
• d) A sulfonic acid Answer: c) An imide

28. The conversion of codeine to morphine is a clinically significant metabolic step catalyzed by which polymorphic enzyme?

• a) CYP3A4
• b) CYP1A2
• c) CYP2D6
• d) UGT1A1 Answer: c) CYP2D6

29. What key structural feature is shared by both nicotine and varenicline?

• a) A seven-membered diazepine ring
• b) A beta-lactam ring
• c) A pyridine ring containing a basic nitrogen
• d) A tropane ester Answer: c) A pyridine ring containing a basic nitrogen

30. The design of long-acting injectable naltrexone involves formulating the drug into:

• a) An oily solution
• b) An enteric-coated tablet
• c) A prodrug that is slowly activated
• d) Biodegradable polymer microspheres Answer: d) Biodegradable polymer microspheres

31. The basicity of the nitrogen atom in most opioid molecules is crucial because at physiological pH, it becomes protonated, allowing for:

• a) An ionic interaction with an acidic residue (e.g., Aspartate) in the opioid receptor.
• b) Covalent bond formation with the receptor.
• c) The molecule to become completely non-polar.
• d) The inhibition of aldehyde dehydrogenase. Answer: a) An ionic interaction with an acidic residue (e.g., Aspartate) in the opioid receptor.

32. The “ether bridge” between C4 and C5 in the morphinan scaffold is critical for:

• a) Making the molecule flexible.
• b) Creating the rigid, T-shaped conformation required for receptor binding.
• c) Ensuring rapid metabolism.
• d) Conferring antagonist activity. Answer: b) Creating the rigid, T-shaped conformation required for receptor binding.

33. The addition of a hydroxyl group at the 14-position of the morphinan skeleton, as in oxycodone and naloxone, generally:

• a) Decreases potency and activity.
• b) Increases potency and activity.
• c) Eliminates all CNS effects.
• d) Makes the drug a liquid at room temperature. Answer: b) Increases potency and activity.

34. The difference between dextroamphetamine and methamphetamine is the presence of:

• a) An extra hydroxyl group on the phenyl ring.
• b) A methyl group on the nitrogen atom in methamphetamine.
• c) A cyclopropyl group on the nitrogen atom in dextroamphetamine.
• d) An ether bridge in the methamphetamine structure. Answer: b) A methyl group on the nitrogen atom in methamphetamine.

35. This N-methylation in methamphetamine leads to:

• a) Decreased potency.
• b) Decreased ability to cross the blood-brain barrier.
• c) Increased lipophilicity and CNS potency compared to amphetamine.
• d) The molecule becoming a full opioid agonist. Answer: c) Increased lipophilicity and CNS potency compared to amphetamine.

36. From a medicinal chemistry perspective, developing a “soft drug” for addiction treatment would involve designing a molecule that:

• a) Is highly potent and has a long duration of action.
• b) Is active but designed to be metabolized quickly into a specific, inactive, and non-toxic compound.
• c) Is a prodrug that requires metabolic activation.
• d) Cannot cross the blood-brain barrier. Answer: b) Is active but designed to be metabolized quickly into a specific, inactive, and non-toxic compound.

37. The LogP (partition coefficient) is a measure of a drug’s lipophilicity. A higher LogP for a substance like fentanyl indicates:

• a) It is more water-soluble.
• b) It will have poor absorption.
• c) It will more readily cross lipid bilayers like the blood-brain barrier.
• d) It is an acid. Answer: c) It will more readily cross lipid bilayers like the blood-brain barrier.

38. The combination product of buprenorphine and naloxone is formulated for sublingual use. What is the medicinal chemistry rationale for adding naloxone?

• a) Naloxone has high sublingual bioavailability and enhances the effect of buprenorphine.
• b) Naloxone has poor sublingual bioavailability and is added to deter intravenous misuse of the crushed tablets.
• c) Naloxone is a flavoring agent.
• d) Naloxone prevents the metabolism of buprenorphine. Answer: b) Naloxone has poor sublingual bioavailability and is added to deter intravenous misuse of the crushed tablets.

39. The chemical basis of the disulfiram-ethanol reaction is the accumulation of acetaldehyde, which is a highly reactive:

• a) Ether
• b) Ketone
• c) Aldehyde
• d) Amine Answer: c) Aldehyde

40. The stereochemistry of nicotine is important, as the naturally occurring and most potent form is the:

• a) (R)-(+)-enantiomer
• b) (S)-(-)-enantiomer
• c) Racemic mixture
• d) Cis-isomer Answer: b) (S)-(-)-enantiomer

41. The structure of topiramate, used off-label for AUD, is a sulfamate-substituted monosaccharide, which is chemically distinct from:

• a) All other anticonvulsants.
• b) Classic neurotransmitter analogues like GABA.
• c) Morphinan-based opioids.
• d) All of the above. Answer: d) All of the above.

42. The metabolism of Lorazepam, Oxazepam, and Temazepam (the “LOT” benzodiazepines) bypasses Phase I oxidation and proceeds directly to which Phase II reaction?

• a) Sulfation
• b) Acetylation
• c) Glucuronidation
• d) Methylation Answer: c) Glucuronidation

43. This metabolic profile makes the “LOT” drugs less dependent on liver function, a key medicinal chemistry consideration for patients with:

• a) Kidney disease
• b) Alcoholic liver disease
• c) Diabetes
• d) Hypertension Answer: b) Alcoholic liver disease

44. The design of a partial agonist like varenicline is a medicinal chemistry strategy that allows the drug to:

• a) Provide some receptor stimulation to reduce cravings while also blocking the effects of a full agonist (nicotine).
• b) Completely block the receptor with no stimulation.
• c) Fully mimic the effect of the endogenous ligand.
• d) Only work when taken intravenously. Answer: a) Provide some receptor stimulation to reduce cravings while also blocking the effects of a full agonist (nicotine).

45. Which functional group on the phenyl ring of morphine is essential for its analgesic activity?

• a) The C3 phenolic hydroxyl group
• b) The C6 allylic hydroxyl group
• c) The N-methyl group
• d) The ether bridge Answer: a) The C3 phenolic hydroxyl group

46. The presence of two basic nitrogen atoms in the varenicline structure allows it to:

• a) Be highly lipophilic.
• b) Be protonated at physiological pH and interact with the nicotinic receptor.
• c) Be rapidly metabolized by MAO.
• d) Inhibit aldehyde dehydrogenase. Answer: b) Be protonated at physiological pH and interact with the nicotinic receptor.

47. From a medicinal chemistry perspective, the development of drugs to treat addiction is challenging because the targets are:

• a) Located only in the peripheral nervous system.
• b) Located in the CNS and require drugs that can cross the blood-brain barrier.
• c) Enzymes that are not well understood.
• d) Receptors that do not bind small molecules. Answer: b) Located in the CNS and require drugs that can cross the blood-brain barrier.

48. The active metabolite of bupropion, hydroxybupropion, is formed via hydroxylation of which part of the molecule?

• a) The aromatic ring
• b) The tert-butyl group
• c) The ketone functional group
• d) The chlorine atom Answer: b) The tert-butyl group

49. The fundamental difference between the structure of an opioid (e.g., morphine) and an opioid antagonist (e.g., naltrexone) lies in the:

• a) Stereochemistry of the C5 carbon.
• b) Substituent on the tertiary nitrogen.
• c) Presence or absence of the C3 hydroxyl group.
• d) Saturation of the C7-C8 double bond. Answer: b) Substituent on the tertiary nitrogen.

50. An understanding of medicinal chemistry is essential for a pharmacist in the field of addiction treatment to:

• a) Predict and explain drug-drug interactions based on metabolic pathways.
• b) Understand the rationale for different formulations (e.g., long-acting injectables).
• c) Explain the basis of a drug’s mechanism of action and side effects.
• d) All of the above. Answer: d) All of the above.