Muscarinic agents, encompassing both agonists and antagonists, interact with muscarinic acetylcholine receptors (mAChRs) found throughout the body, including the airways, heart, and gastrointestinal tract. In respiratory medicine, muscarinic antagonists (anticholinergics) are particularly important for managing conditions like COPD and asthma by inducing bronchodilation. The chemical structures of these agents are key to their affinity, selectivity, duration of action, and pharmacokinetic profiles. For PharmD students, a solid understanding of the medicinal chemistry of muscarinic agents, especially the antagonists used in respiratory care, is crucial for appreciating their therapeutic applications and structure-activity relationships (SAR). This MCQ quiz will explore these essential medicinal chemistry principles.
1. Acetylcholine, the endogenous neurotransmitter for muscarinic receptors, possesses which key structural feature essential for its activity?
- A. A steroid nucleus
- B. A quaternary ammonium group and an ester linkage
- C. A dihydropyridine ring
- D. A catechol moiety
Answer: B. A quaternary ammonium group and an ester linkage
2. According to Ing’s Rule of Five, for optimal muscarinic agonist activity, there should be no more than five atoms between the:
- A. Ester oxygen and the carbonyl carbon.
- B. Quaternary nitrogen and the terminal hydrogen of the ester alkyl group.
- C. Aromatic ring and the ester group.
- D. Two methyl groups on the nitrogen.
Answer: B. Quaternary nitrogen and the terminal hydrogen of the ester alkyl group.
3. Methacholine, a muscarinic agonist, is structurally different from acetylcholine by the presence of a:
- A. Carbamate ester instead of an acetate ester.
- B. Methyl group on the β-carbon of the ethanolamine backbone.
- C. Tertiary amine instead of a quaternary ammonium.
- D. Thioester linkage.
Answer: B. Methyl group on the β-carbon of the ethanolamine backbone. (This confers some M-selectivity over N and slows hydrolysis).
4. Carbachol and Bethanechol are muscarinic agonists that are more resistant to hydrolysis by acetylcholinesterase than acetylcholine because they possess a:
- A. Longer ethylene bridge
- B. Tertiary amine group
- C. Carbamate ester group instead of an acetate ester
- D. Phenyl ring
Answer: C. Carbamate ester group instead of an acetate ester
5. Atropine, a prototypical muscarinic antagonist, is a naturally occurring tropane alkaloid. Its structure is an ester of tropine (a bicyclic aminoalcohol) and:
- A. Acetic acid
- B. Tropic acid (α-phenyl-β-hydroxypropionic acid)
- C. Mandelic acid
- D. Benzoic acid
Answer: B. Tropic acid (α-phenyl-β-hydroxypropionic acid)
6. The presence of a quaternary ammonium group in inhaled muscarinic antagonists like ipratropium bromide and tiotropium bromide primarily serves to:
- A. Increase their lipophilicity and CNS penetration.
- B. Enhance their oral bioavailability.
- C. Limit their systemic absorption from the lungs and GI tract, thus localizing their action and reducing systemic side effects.
- D. Make them more susceptible to hydrolysis by esterases.
Answer: C. Limit their systemic absorption from the lungs and GI tract, thus localizing their action and reducing systemic side effects.
7. Ipratropium bromide is a short-acting muscarinic antagonist (SAMA). It is a synthetic quaternary ammonium derivative of:
- A. Scopolamine
- B. Atropine (specifically N-isopropylatropine)
- C. Pilocarpine
- D. Acetylcholine
Answer: B. Atropine (specifically N-isopropylatropine)
8. Tiotropium bromide is a long-acting muscarinic antagonist (LAMA). Its prolonged duration of action is attributed to its:
- A. Rapid association with and rapid dissociation from all muscarinic receptor subtypes.
- B. Slow dissociation kinetics, particularly from M3 (and M1) muscarinic receptors, compared to M2 receptors.
- C. Conversion to multiple long-acting active metabolites.
- D. Irreversible binding to muscarinic receptors.
Answer: B. Slow dissociation kinetics, particularly from M3 (and M1) muscarinic receptors, compared to M2 receptors.
9. The general pharmacophore for muscarinic antagonists often includes a cationic head (quaternary or protonated tertiary amine), an ester or ether linkage, and:
- A. Small, polar alkyl groups attached to the α-carbon of the acid moiety.
- B. At least one, preferably two, bulky, hydrophobic ring systems (e.g., phenyl, cyclohexyl, thiophene) attached to the α-carbon of the acid moiety.
- C. A catecholamine structure.
- D. A long polyethylene glycol chain.
Answer: B. At least one, preferably two, bulky, hydrophobic ring systems (e.g., phenyl, cyclohexyl, thiophene) attached to the α-carbon of the acid moiety.
10. Aclidinium bromide, a LAMA, is designed as a “soft drug.” This means it is:
- A. Highly resistant to metabolism.
- B. Active as administered and rapidly hydrolyzed in plasma to inactive metabolites, minimizing systemic exposure and side effects.
- C. Only effective when administered orally.
- D. A prodrug that requires activation in the lungs.
Answer: B. Active as administered and rapidly hydrolyzed in plasma to inactive metabolites, minimizing systemic exposure and side effects.
11. Glycopyrronium bromide (glycopyrrolate) is a quaternary ammonium muscarinic antagonist. Its structure features a(n):
- A. Tropane ring system
- B. Aminoalcohol ester with cyclopentyl and phenyl groups on the acid portion
- C. Thiophene ring system
- D. Dihydropyridine ring
Answer: B. Aminoalcohol ester with cyclopentyl and phenyl groups on the acid portion
12. Umeclidinium bromide is a LAMA with a complex quinuclidine-based structure. Its long duration of action is primarily due to:
- A. Slow metabolic inactivation.
- B. High affinity and slow dissociation from muscarinic receptors.
- C. Prodrug activation in the lungs.
- D. Enterohepatic recirculation.
Answer: B. High affinity and slow dissociation from muscarinic receptors.
13. The ester functional group present in many muscarinic antagonists (e.g., ipratropium, tiotropium, aclidinium, glycopyrronium) is important for:
- A. Only increasing water solubility.
- B. Acting as a key interaction point (hydrogen bond acceptor) within the muscarinic receptor binding site and influencing pharmacokinetic properties.
- C. Making the molecule resistant to all hydrolysis.
- D. Conferring beta-2 agonist activity.
Answer: B. Acting as a key interaction point (hydrogen bond acceptor) within the muscarinic receptor binding site and influencing pharmacokinetic properties.
14. The hydroxyl group on the acid portion (e.g., in tropic acid of atropine, or the α-hydroxyacid moiety in glycopyrronium) of many muscarinic antagonists is thought to:
- A. Decrease receptor binding affinity.
- B. Form a hydrogen bond with a specific site on the muscarinic receptor, enhancing binding.
- C. Be the primary site of metabolic inactivation.
- D. Make the molecule highly acidic.
Answer: B. Form a hydrogen bond with a specific site on the muscarinic receptor, enhancing binding.
15. Atropine is a racemic mixture of d-hyoscyamine and l-hyoscyamine. The anticholinergic activity resides primarily in:
- A. d-hyoscyamine
- B. l-hyoscyamine (S-hyoscyamine)
- C. Both enantiomers equally
- D. The racemic mixture is required for synergy.
Answer: B. l-hyoscyamine (S-hyoscyamine)
16. The quaternization of the nitrogen atom in ipratropium and tiotropium (from their tertiary amine precursors) results in:
- A. Increased lipophilicity and CNS penetration.
- B. Decreased polarity and enhanced oral absorption.
- C. A permanent positive charge, leading to increased polarity, poor membrane permeability, and localized action when inhaled.
- D. Conversion to a muscarinic agonist.
Answer: C. A permanent positive charge, leading to increased polarity, poor membrane permeability, and localized action when inhaled.
17. Tiotropium contains two thiophene rings in its acid moiety. These rings contribute to:
- A. Its high water solubility.
- B. Its lipophilicity and specific interactions within the M3 receptor binding pocket, contributing to its slow dissociation.
- C. Its susceptibility to rapid metabolism.
- D. Its conversion to a SAMA.
Answer: B. Its lipophilicity and specific interactions within the M3 receptor binding pocket, contributing to its slow dissociation.
18. The bromide counterion in ipratropium bromide, tiotropium bromide, etc., is present because:
- A. It is essential for pharmacological activity.
- B. These drugs are quaternary ammonium salts, and bromide is a common pharmaceutically acceptable counterion to form a stable salt.
- C. Bromide itself has anticholinergic effects.
- D. It facilitates oral absorption.
Answer: B. These drugs are quaternary ammonium salts, and bromide is a common pharmaceutically acceptable counterion to form a stable salt.
19. The primary route of elimination for inhaled quaternary ammonium muscarinic antagonists like ipratropium and tiotropium (the small fraction that gets systemically absorbed) is:
- A. Extensive hepatic metabolism followed by biliary excretion.
- B. Primarily renal excretion as unchanged drug and some metabolites (as systemic absorption is low).
- C. Exhalation via the lungs.
- D. Complete metabolism within the lung tissue.
Answer: B. Primarily renal excretion as unchanged drug and some metabolites (as systemic absorption is low).
20. Aclidinium bromide’s design as a “soft drug” involves rapid hydrolysis of its ester linkage in human plasma to form:
- A. Two active metabolites.
- B. An inactive alcohol derivative and an inactive carboxylic acid derivative.
- C. Tiotropium.
- D. Atropine.
Answer: B. An inactive alcohol derivative and an inactive carboxylic acid derivative.
21. Compared to atropine (a tertiary amine), ipratropium (a quaternary amine) has:
- A. Greater CNS penetration and more central side effects.
- B. Similar CNS penetration.
- C. Significantly reduced CNS penetration and fewer central anticholinergic side effects when administered by inhalation.
- D. Higher oral bioavailability.
Answer: C. Significantly reduced CNS penetration and fewer central anticholinergic side effects when administered by inhalation.
22. The M3 muscarinic receptor subtype is the primary target for anticholinergic bronchodilators because it is predominantly located on:
- A. Cardiac pacemaker cells, slowing heart rate.
- B. Airway smooth muscle, mediating bronchoconstriction, and submucosal glands.
- C. Presynaptic autonomic nerve terminals, inhibiting acetylcholine release.
- D. Gastric parietal cells, reducing acid secretion.
Answer: B. Airway smooth muscle, mediating bronchoconstriction, and submucosal glands.
23. The “tropane” ring system found in atropine and scopolamine is a:
- A. Simple piperidine ring
- B. Bicyclic [3.2.1] nitrogen-containing structure
- C. Monocyclic azepine ring
- D. Thiazolidine ring
Answer: B. Bicyclic [3.2.1] nitrogen-containing structure
24. What structural feature is common to acetylcholine and muscarinic antagonists like ipratropium that is responsible for initial binding to the anionic site of the muscarinic receptor?
- A. The ester group
- B. The hydroxyl group
- C. The cationic nitrogen center (quaternary or protonated tertiary amine)
- D. The aromatic rings
Answer: C. The cationic nitrogen center (quaternary or protonated tertiary amine)
25. The difference between an agonist (like acetylcholine) and an antagonist (like atropine) at the muscarinic receptor, from a structural interaction perspective, is that antagonists typically:
- A. Are much smaller molecules that only partially fill the binding site.
- B. Bind to an allosteric site, causing a conformational change that prevents agonist binding.
- C. Possess bulky, hydrophobic groups that bind to accessory regions of the receptor, preventing the conformational change necessary for receptor activation by an agonist.
- D. Form irreversible covalent bonds with the receptor.
Answer: C. Possess bulky, hydrophobic groups that bind to accessory regions of the receptor, preventing the conformational change necessary for receptor activation by an agonist.
26. Revefenacin is a LAMA administered by nebulization. Its chemical structure is distinct from the tropane or quinuclidine-based LAMAs and is a:
- A. Biphenyl derivative (specifically a ((diphenylacetyl)oxy)ethyl)amino compound).
- B. Thiophene derivative.
- C. Steroidal compound.
- D. Saligenin derivative.
Answer: A. Biphenyl derivative (specifically a ((diphenylacetyl)oxy)ethyl)amino compound).
27. The ester bond in aclidinium is susceptible to hydrolysis by plasma esterases (e.g., butyrylcholinesterase). This rapid systemic inactivation contributes to its:
- A. Long duration of action in the lungs.
- B. Favorable systemic safety profile, as any absorbed drug is quickly inactivated.
- C. Need for frequent daily dosing.
- D. High CNS penetration.
Answer: B. Favorable systemic safety profile, as any absorbed drug is quickly inactivated.
28. The presence of two thiophene rings in the “acid” portion of tiotropium, compared to two phenyl rings in some other antagonists, can influence:
- A. Only its color.
- B. Its lipophilicity, receptor binding interactions (e.g., hydrophobic pockets), and overall pharmacokinetic/pharmacodynamic profile.
- C. Its susceptibility to COMT.
- D. Its ability to form a quaternary salt.
Answer: B. Its lipophilicity, receptor binding interactions (e.g., hydrophobic pockets), and overall pharmacokinetic/pharmacodynamic profile.
29. From a medicinal chemistry SAR standpoint, the distance between the cationic nitrogen and the ester/ether oxygen in muscarinic antagonists is important for:
- A. Determining its color.
- B. Optimal interaction with the receptor, roughly corresponding to the distance in acetylcholine.
- C. Its susceptibility to MAO.
- D. Its ability to cross the blood-brain barrier.
Answer: B. Optimal interaction with the receptor, roughly corresponding to the distance in acetylcholine. (Though antagonists are larger overall).
30. Hydrolysis of the ester group in atropine yields tropine and tropic acid. This metabolic process leads to:
- A. A more potent anticholinergic compound.
- B. Loss of anticholinergic activity, as the intact ester is required.
- C. Conversion to a muscarinic agonist.
- D. No change in activity.
Answer: B. Loss of anticholinergic activity, as the intact ester is required.
31. The development of LAMAs from SAMAs like ipratropium involved medicinal chemistry strategies to:
- A. Decrease receptor affinity.
- B. Increase the rate of dissociation from muscarinic receptors.
- C. Achieve prolonged receptor occupancy, often through slower dissociation kinetics or favorable physicochemical properties for lung retention.
- D. Increase systemic absorption.
Answer: C. Achieve prolonged receptor occupancy, often through slower dissociation kinetics or favorable physicochemical properties for lung retention.
32. What role does the hydroxyl group on the α-carbon of the acid moiety (e.g., in tropic acid of atropine or the α-hydroxy-α,α-diphenylacetate of glycopyrronium) generally play in muscarinic antagonist activity?
- A. It decreases binding affinity due to increased polarity.
- B. It often enhances binding through hydrogen bonding with the receptor.
- C. It is the primary site for metabolic N-dealkylation.
- D. It makes the molecule a strong acid.
Answer: B. It often enhances binding through hydrogen bonding with the receptor.
33. The design of inhaled muscarinic antagonists focuses on maximizing local bronchodilation while minimizing systemic anticholinergic side effects (dry mouth, blurred vision, urinary retention). Quaternization of the nitrogen is a key strategy for this because:
- A. It makes the drug more lipophilic.
- B. It creates a permanent positive charge, reducing systemic absorption from the lungs and GI tract.
- C. It increases the drug’s potency at M2 receptors.
- D. It converts the antagonist into an agonist.
Answer: B. It creates a permanent positive charge, reducing systemic absorption from the lungs and GI tract.
34. Scopolamine (hyoscine) is another tropane alkaloid muscarinic antagonist. It differs structurally from atropine by the presence of an:
- A. Additional methyl group on the nitrogen.
- B. Epoxy group across the tropane ring (C6-C7).
- C. Ester with mandelic acid instead of tropic acid.
- D. Absence of the hydroxyl group in the acid moiety.
Answer: B. Epoxy group across the tropane ring (C6-C7). This also makes it more lipid-soluble and allows for greater CNS penetration than atropine.
35. Which part of the acetylcholine molecule is primarily responsible for its rapid hydrolysis by acetylcholinesterase?
- A. The quaternary ammonium head
- B. The ethylene bridge
- C. The acetate ester linkage
- D. The methyl groups on the nitrogen
Answer: C. The acetate ester linkage
36. The chemical stability of ester-containing muscarinic antagonists like aclidinium can be a formulation challenge. They are susceptible to:
- A. Oxidation primarily
- B. Hydrolysis, especially at non-neutral pH or in the presence of esterases
- C. Reduction
- D. N-dealkylation as the primary instability pathway
Answer: B. Hydrolysis, especially at non-neutral pH or in the presence of esterases
37. Many muscarinic antagonists are chiral molecules. If a racemic mixture is used, it means:
- A. Only one enantiomer is present.
- B. Both enantiomers are present in a 1:1 ratio, and they may have different affinities for the receptor or different metabolic fates.
- C. The drug is achiral.
- D. The drug has multiple geometric isomers.
Answer: B. Both enantiomers are present in a 1:1 ratio, and they may have different affinities for the receptor or different metabolic fates.
38. The bulky, hydrophobic rings (e.g., phenyl, thiophene) in the “acid” portion of muscarinic antagonists are thought to interact with which regions of the muscarinic receptor?
- A. The primary anionic binding site for the cationic head.
- B. Hydrophobic pockets or accessory binding sites distinct from the acetylcholine binding site, contributing to antagonistic properties.
- C. Only the extracellular N-terminus.
- D. The intracellular G-protein coupling domain.
Answer: B. Hydrophobic pockets or accessory binding sites distinct from the acetylcholine binding site, contributing to antagonistic properties.
39. The selection of a specific salt form (e.g., bromide) for quaternary ammonium muscarinic antagonists like ipratropium bromide is based on achieving:
- A. The highest possible lipophilicity.
- B. Optimal physicochemical properties for formulation, stability, and pharmaceutical use.
- C. A specific color for the final drug product.
- D. Resistance to all metabolism.
Answer: B. Optimal physicochemical properties for formulation, stability, and pharmaceutical use.
40. From a medicinal chemistry perspective, developing a LAMA with M3 receptor subtype selectivity over M2 receptors in the airways would be advantageous because:
- A. M2 receptors mediate bronchodilation.
- B. M3 receptors mediate bronchoconstriction and mucus secretion (target for blockade), while M2 autoreceptors inhibit further acetylcholine release (undesirable to block).
- C. M3 receptors are only found systemically.
- D. M2 receptors are responsible for anti-inflammatory effects.
Answer: B. M3 receptors mediate bronchoconstriction and mucus secretion (target for blockade), while M2 autoreceptors inhibit further acetylcholine release (undesirable to block). (Tiotropium has kinetic selectivity for M3/M1 over M2).
41. The basicity of the nitrogen atom (pKa) in tertiary amine muscarinic antagonists is important because it determines:
- A. Their color.
- B. The degree of protonation (and thus positive charge) at physiological pH, which influences receptor binding and membrane permeability.
- C. Their susceptibility to ester hydrolysis.
- D. Their ability to form covalent bonds.
Answer: B. The degree of protonation (and thus positive charge) at physiological pH, which influences receptor binding and membrane permeability.
42. Which of the following structural features is NOT typically part of the classical pharmacophore for ester-containing muscarinic antagonists derived from aminoalcohols?
- A. A cationic head (quaternary or protonatable tertiary amine)
- B. A large, bulky acidic moiety with hydrophobic rings
- C. An ester linkage (or sometimes ether)
- D. A catecholamine (dihydroxybenzene) system
Answer: D. A catecholamine (dihydroxybenzene) system
43. The transition from naturally occurring tropane alkaloids (like atropine) to synthetic quaternary ammonium derivatives (like ipratropium) for inhalation was a key medicinal chemistry strategy to:
- A. Increase potency at all muscarinic receptor subtypes.
- B. Improve oral bioavailability.
- C. Reduce systemic absorption and CNS side effects when administered by inhalation.
- D. Make the compounds more stable to light.
Answer: C. Reduce systemic absorption and CNS side effects when administered by inhalation.
44. The replacement of phenyl rings with thiophene rings in the acid moiety of tiotropium (compared to some earlier antagonists) was a modification that:
- A. Decreased its affinity for muscarinic receptors.
- B. Contributed to its unique receptor binding kinetics and prolonged duration of action.
- C. Made it a potent beta-2 agonist.
- D. Increased its water solubility significantly.
Answer: B. Contributed to its unique receptor binding kinetics and prolonged duration of action.
45. The medicinal chemistry goal of designing “soft” anticholinergics like aclidinium is to create molecules that are:
- A. Highly stable in plasma.
- B. Active locally in the lungs but rapidly hydrolyzed to inactive metabolites upon systemic absorption.
- C. Potent agonists.
- D. Exclusively eliminated by the kidneys without metabolism.
Answer: B. Active locally in the lungs but rapidly hydrolyzed to inactive metabolites upon systemic absorption.
46. The bond connecting the sugar(s) to the aglycone in a cardiac glycoside is an O-glycosidic bond. The bond linking the aminoalcohol to the acid moiety in many muscarinic antagonists (e.g., atropine, ipratropium) is a(n):
- A. Amide bond
- B. Ester bond
- C. Ether bond
- D. Carbon-carbon bond
Answer: B. Ester bond
47. What structural feature largely dictates that inhaled quaternary ammonium muscarinic antagonists will have minimal direct CNS effects?
- A. Their high lipophilicity
- B. Their permanent positive charge, which severely limits blood-brain barrier penetration
- C. Their rapid metabolism in the brain
- D. Their small molecular size
Answer: B. Their permanent positive charge, which severely limits blood-brain barrier penetration
48. The “onium” suffix in drug names like ipratropium, tiotropium, aclidinium, umeclidinium, and glycopyrronium often indicates the presence of a:
- A. Carboxylic acid group
- B. Sulfhydryl group
- C. Quaternary ammonium (cationic) center
- D. Ketone group
Answer: C. Quaternary ammonium (cationic) center
49. From a SAR perspective, if the bulky hydrophobic groups on the acid moiety of a muscarinic antagonist were replaced with small alkyl groups (e.g., methyl), the compound would likely:
- A. Become a more potent antagonist.
- B. Lose significant antagonistic activity or potentially gain agonist properties.
- C. Have a much longer duration of action.
- D. Become orally bioavailable if it wasn’t before.
Answer: B. Lose significant antagonistic activity or potentially gain agonist properties.
50. The medicinal chemistry of inhaled LAMAs like tiotropium and umeclidinium has focused on achieving prolonged bronchodilation through high receptor affinity and:
- A. Rapid association and rapid dissociation from the receptor.
- B. Slow dissociation from M3 (and M1) muscarinic receptors.
- C. Irreversible covalent binding to M3 receptors.
- D. Activation of M2 autoreceptors.
Answer: B. Slow dissociation from M3 (and M1) muscarinic receptors.