Short-acting beta2-agonists (SABAs) are indispensable quick-relief medications for bronchospasm in asthma and Chronic Obstructive Pulmonary Disease (COPD). Their ability to rapidly relax airway smooth muscle is a direct consequence of their chemical structures, which allow for selective interaction with β2-adrenergic receptors. For PharmD students, understanding the medicinal chemistry of SABAs—including their core pharmacophore, structure-activity relationships (SAR) that govern selectivity and duration, stereochemical considerations, and metabolic pathways—is crucial for appreciating their therapeutic use, predicting potential side effects, and understanding their place in respiratory care. This MCQ quiz will explore the key medicinal chemistry aspects of these important bronchodilators.
1. Short-acting beta2-agonists (SABAs) are structurally related to which endogenous neurotransmitter?
- A. Acetylcholine
- B. Serotonin
- C. Epinephrine (Adrenaline)
- D. Histamine
Answer: C. Epinephrine (Adrenaline)
2. The core pharmacophore of most beta2-agonists, including SABAs, is a(n):
- A. Steroid nucleus
- B. Phenylethanolamine or arylethanolamine structure
- C. Thienopyridine ring
- D. Dihydropyridine ring
Answer: B. Phenylethanolamine or arylethanolamine structure
3. For optimal beta2-adrenergic receptor agonism, which group on the ethanolamine side chain (-CH(OH)-CH2-NH-R) is essential for direct interaction with the receptor and usually has a specific stereochemical requirement?
- A. The N-alkyl substituent (R)
- B. The β-hydroxyl group (-CH(OH)-)
- C. The α-carbon
- D. The ethylene bridge (-CH2-CH2-)
Answer: B. The β-hydroxyl group (-CH(OH)-)
4. The (R)-enantiomer of albuterol (salbutamol) is known as levalbuterol. The (R)-enantiomer is considered to be:
- A. Primarily responsible for the adverse effects of racemic albuterol.
- B. The enantiomer primarily responsible for the bronchodilatory activity.
- C. An inactive metabolite of albuterol.
- D. A potent alpha-adrenergic agonist.
Answer: B. The enantiomer primarily responsible for the bronchodilatory activity.
5. Modification of the catechol ring (3,4-dihydroxybenzene) of older beta-agonists like isoproterenol was crucial to develop SABAs that are:
- A. More selective for alpha-receptors.
- B. Resistant to metabolic inactivation by Catechol-O-Methyltransferase (COMT) and have improved β2-selectivity.
- C. Only active when administered intravenously.
- D. Longer acting than LABAs.
Answer: B. Resistant to metabolic inactivation by Catechol-O-Methyltransferase (COMT) and have improved β2-selectivity.
6. Albuterol (salbutamol) has a “saligenin” aromatic ring system. This means its hydroxyl groups are at which positions on the benzene ring relative to the ethanolamine side chain attachment?
- A. 3,4-dihydroxy (catechol)
- B. 3,5-dihydroxy (resorcinol)
- C. 3-hydroxymethyl-4-hydroxy
- D. 4-hydroxy only
Answer: C. 3-hydroxymethyl-4-hydroxy
7. Terbutaline and metaproterenol are SABAs that possess which type of aromatic ring system, conferring COMT resistance and some β2-selectivity?
- A. Catechol
- B. Saligenin
- C. Resorcinol (3,5-dihydroxybenzene)
- D. Indole
Answer: C. Resorcinol (3,5-dihydroxybenzene)
8. The size and nature of the N-alkyl substituent (R in -NH-R) on the ethanolamine side chain of beta-agonists significantly influences receptor selectivity. A bulky N-substituent, like a tertiary butyl group found in albuterol and terbutaline, generally favors:
- A. Alpha-1 adrenergic receptor selectivity
- B. Beta-1 adrenergic receptor selectivity
- C. Beta-2 adrenergic receptor selectivity
- D. Non-selective beta-agonism similar to isoproterenol
Answer: C. Beta-2 adrenergic receptor selectivity
9. Isoproterenol, an older beta-agonist, has an isopropyl group as its N-substituent. This makes it:
- A. Selective for beta-2 receptors only.
- B. A non-selective beta-agonist (acting on both β1 and β2 receptors).
- C. Selective for alpha receptors.
- D. Resistant to COMT metabolism.
Answer: B. A non-selective beta-agonist (acting on both β1 and β2 receptors).
10. The short duration of action of SABAs like albuterol is primarily due to:
- A. Their irreversible binding to the beta-2 receptor.
- B. Their chemical instability in the airways.
- C. Their pharmacokinetic properties including relatively rapid metabolism (e.g., sulfation) and clearance.
- D. Their conversion to long-acting active metabolites.
Answer: C. Their pharmacokinetic properties including relatively rapid metabolism (e.g., sulfation) and clearance.
11. Levalbuterol is the pure (R)-enantiomer of albuterol. It was developed based on the hypothesis that the (S)-enantiomer of albuterol might:
- A. Be more potent as a bronchodilator.
- B. Contribute to some adverse effects or even paradoxical bronchoconstriction, though this is debated.
- C. Be responsible for the drug’s sweet taste.
- D. Have a longer duration of action.
Answer: B. Contribute to some adverse effects or even paradoxical bronchoconstriction, though this is debated.
12. Pirbuterol, another SABA, has a pyridine ring instead of a benzene ring as its aromatic system and a hydroxymethyl group on the nitrogen. The pyridine ring aims to:
- A. Increase alpha-1 selectivity.
- B. Provide similar electronic properties to a substituted benzene while potentially altering metabolism or receptor interaction.
- C. Make the compound extremely lipophilic.
- D. Ensure irreversible receptor binding.
Answer: B. Provide similar electronic properties to a substituted benzene while potentially altering metabolism or receptor interaction.
13. The primary route of administration for SABAs for asthma/COPD quick relief is:
- A. Oral tablet
- B. Intravenous injection
- C. Inhalation (e.g., MDI, nebulizer)
- D. Transdermal patch
Answer: C. Inhalation (e.g., MDI, nebulizer) (This maximizes local lung delivery and minimizes systemic side effects).
14. The basic amino group in the ethanolamine side chain of SABAs is important because at physiological pH, it is predominantly __________, allowing for ionic interaction with the receptor.
- A. Non-ionized
- B. Protonated (cationic)
- C. Oxidized
- D. Reduced
Answer: B. Protonated (cationic)
15. Which structural feature in albuterol makes it resistant to metabolism by Catechol-O-Methyltransferase (COMT), unlike isoproterenol?
- A. The N-tertiary butyl group
- B. The replacement of the 3-hydroxyl of a catechol with a 3-hydroxymethyl group (saligenin derivative)
- C. The (R)-configuration at the chiral carbon
- D. Its formulation as a sulfate salt
Answer: B. The replacement of the 3-hydroxyl of a catechol with a 3-hydroxymethyl group (saligenin derivative)
16. The hydroxyl group at the chiral carbon of the ethanolamine side chain must have which stereochemical configuration for optimal β2-agonist activity?
- A. (S)-configuration
- B. (R)-configuration
- C. Racemic mixture is always more active
- D. Configuration is irrelevant
Answer: B. (R)-configuration
17. The major metabolic pathway for albuterol after systemic absorption is:
- A. Oxidation by CYP3A4
- B. N-dealkylation
- C. Conjugation, primarily sulfation of the phenolic hydroxyl group
- D. Hydrolysis of an ester bond
Answer: C. Conjugation, primarily sulfation of the phenolic hydroxyl group
18. Terbutaline contains a resorcinol (3,5-dihydroxybenzene) ring. This structural feature, compared to a catechol ring, provides:
- A. Increased susceptibility to COMT.
- B. Resistance to COMT and some degree of β2 selectivity.
- C. Enhanced alpha-1 agonist activity.
- D. A much shorter duration of action.
Answer: B. Resistance to COMT and some degree of β2 selectivity.
19. What is a key medicinal chemistry strategy to increase β2-receptor selectivity in phenylethanolamine derivatives?
- A. Decreasing the size of the N-alkyl substituent.
- B. Increasing the size of the N-alkyl substituent (e.g., isopropyl, tert-butyl).
- C. Replacing the aromatic hydroxyl groups with methyl groups.
- D. Introducing a halogen at the α-carbon.
Answer: B. Increasing the size of the N-alkyl substituent (e.g., isopropyl, tert-butyl).
20. The “ethanolamine” portion of SABAs (-CH(OH)-CH2-NH-R) is crucial for receptor interaction. The hydroxyl group and the amino group are thought to form hydrogen bonds with specific amino acid residues in the β2-receptor binding site, such as:
- A. Cysteine and methionine
- B. Serine and aspartate residues
- C. Phenylalanine and tryptophan
- D. Glycine and alanine
Answer: B. Serine and aspartate residues
21. Modifications of the aromatic ring from a catechol (like in isoproterenol) to a saligenin (albuterol) or resorcinol (terbutaline) were primarily aimed at:
- A. Increasing water solubility for IV use.
- B. Improving metabolic stability (resistance to COMT) and enhancing β2 selectivity.
- C. Decreasing potency to reduce side effects.
- D. Making the compounds suitable for transdermal delivery.
Answer: B. Improving metabolic stability (resistance to COMT) and enhancing β2 selectivity.
22. The presence of a tertiary butyl group on the nitrogen atom of albuterol and terbutaline, compared to a smaller group like methyl, contributes to:
- A. Greater alpha-1 agonist activity
- B. Greater beta-2 selectivity and reduced susceptibility to MAO (though MAO is less critical for these structures)
- C. Shorter duration of action
- D. Increased metabolism by COMT
Answer: B. Greater beta-2 selectivity and reduced susceptibility to MAO (though MAO is less critical for these structures)
23. Levalbuterol contains only the (R)-enantiomer. The (S)-enantiomer of albuterol has been suggested in some studies to:
- A. Be equally effective as a bronchodilator.
- B. Be inert or potentially have some pro-inflammatory or paradoxical bronchoconstricting effects.
- C. Be responsible for the rapid onset of action.
- D. Be more rapidly metabolized than the (R)-enantiomer.
Answer: B. Be inert or potentially have some pro-inflammatory or paradoxical bronchoconstricting effects. (This is a topic of some debate, but the rationale for levalbuterol’s development).
24. From a medicinal chemistry perspective, an ideal SABA for inhalation would possess:
- A. High lipophilicity for systemic distribution and long duration.
- B. Sufficient aqueous solubility for nebulization/MDI formulation, high β2-receptor affinity/efficacy, and rapid metabolism/clearance once systemically absorbed to minimize side effects.
- C. Irreversible binding to the β2-receptor.
- D. No N-alkyl substituent for maximum potency.
Answer: B. Sufficient aqueous solubility for nebulization/MDI formulation, high β2-receptor affinity/efficacy, and rapid metabolism/clearance once systemically absorbed to minimize side effects.
25. The positive charge on the protonated amine group of SABAs at physiological pH allows for a key ionic interaction with which type of amino acid residue in the β2-adrenergic receptor binding site?
- A. A basic residue (e.g., lysine)
- B. An acidic residue (e.g., aspartate)
- C. A nonpolar residue (e.g., leucine)
- D. A cysteine residue (for disulfide bonding)
Answer: B. An acidic residue (e.g., aspartate)
26. The short duration of action of SABAs like albuterol (typically 4-6 hours) is a defining characteristic. This is primarily related to their:
- A. Chemical structure favoring rapid dissociation from the receptor and subsequent metabolism/elimination.
- B. Formulation as inhaled powders only.
- C. Very slow absorption from the lungs.
- D. Conversion to long-acting antagonists.
Answer: A. Chemical structure favoring rapid dissociation from the receptor and subsequent metabolism/elimination.
27. Bitolterol was an older SABA that was a prodrug. It was a di-p-toluate ester of colterol (N-tert-butylnorepinephrine). Hydrolysis by esterases yielded active colterol. The prodrug approach was used to:
- A. Increase water solubility.
- B. Improve oral bioavailability and protect the catechol from COMT degradation prior to absorption/action.
- C. Decrease potency.
- D. Convert it into an inhaled corticosteroid.
Answer: B. Improve oral bioavailability and protect the catechol from COMT degradation prior to absorption/action. (And prolong action).
28. The structural difference between epinephrine (N-methyl) and isoproterenol (N-isopropyl) primarily accounts for isoproterenol’s:
- A. Greater alpha-adrenergic activity.
- B. Greater beta-adrenergic activity (β1 and β2) and reduced alpha activity.
- C. Resistance to COMT.
- D. Longer duration of action.
Answer: B. Greater beta-adrenergic activity (β1 and β2) and reduced alpha activity.
29. Metaproterenol has hydroxyl groups at positions 3 and 5 of its benzene ring. This resorcinol structure, compared to a catechol, is:
- A. More susceptible to COMT.
- B. Less susceptible to COMT, allowing for oral activity and longer duration than isoproterenol.
- C. A potent alpha-agonist.
- D. Only active when inhaled.
Answer: B. Less susceptible to COMT, allowing for oral activity and longer duration than isoproterenol.
30. The development of β2-selective agonists involved medicinal chemistry strategies focused on modifying the N-alkyl substituent and the __________ to reduce cardiac (β1) side effects and improve metabolic stability.
- A. α-carbon of the ethanolamine side chain
- B. Aromatic ring hydroxyl group pattern
- C. β-hydroxyl group
- D. Amine pKa only
Answer: B. Aromatic ring hydroxyl group pattern
31. Which SABA is formulated as a single (R)-enantiomer product?
- A. Racemic albuterol
- B. Terbutaline
- C. Levalbuterol
- D. Metaproterenol
Answer: C. Levalbuterol
32. The binding of a SABA to the β2-adrenergic receptor, a G-protein coupled receptor (GPCR), ultimately leads to:
- A. Decreased intracellular cGMP.
- B. Activation of adenylyl cyclase and increased intracellular cAMP.
- C. Inhibition of protein kinase A.
- D. Opening of ligand-gated sodium channels.
Answer: B. Activation of adenylyl cyclase and increased intracellular cAMP.
33. If the β-hydroxyl group of a phenylethanolamine SABA is absent or in the (S)-configuration, what is the likely impact on its β2-agonist activity?
- A. Potency is significantly increased.
- B. Activity is significantly reduced or lost.
- C. β1-selectivity is enhanced.
- D. Duration of action is prolonged.
Answer: B. Activity is significantly reduced or lost.
34. The formulation of SABAs for inhalation (e.g., as sulfate or hydrochloride salts) is important for their:
- A. Conversion to active metabolites.
- B. Stability, solubility, and delivery characteristics from the inhaler device.
- C. Ability to cause systemic side effects.
- D. Irreversible binding to the receptor.
Answer: B. Stability, solubility, and delivery characteristics from the inhaler device.
35. What is the key structural difference between terbutaline and albuterol that affects their aromatic ring substitution pattern?
- A. Terbutaline has a catechol ring; albuterol has a resorcinol ring.
- B. Terbutaline has a resorcinol ring (3,5-dihydroxy); albuterol has a saligenin ring (3-CH2OH, 4-OH).
- C. Both have identical aromatic ring systems.
- D. Terbutaline has a pyridine ring; albuterol has a benzene ring.
Answer: B. Terbutaline has a resorcinol ring (3,5-dihydroxy); albuterol has a saligenin ring (3-CH2OH, 4-OH).
36. The medicinal chemistry goal of creating β2-selective agonists was to minimize which type of side effects associated with non-selective beta-agonists like isoproterenol?
- A. Bronchoconstriction
- B. Cardiac side effects (e.g., tachycardia, palpitations) due to β1 stimulation
- C. Gastrointestinal upset
- D. Sedation
Answer: B. Cardiac side effects (e.g., tachycardia, palpitations) due to β1 stimulation
37. Why are SABAs like albuterol typically effective for only 4-6 hours?
- A. They form irreversible covalent bonds with the receptor.
- B. Their chemical structure allows for relatively rapid dissociation from the receptor and they are subject to metabolism and/or clearance.
- C. They are converted to long-acting antagonists after 6 hours.
- D. They are very poorly absorbed from the lungs.
Answer: B. Their chemical structure allows for relatively rapid dissociation from the receptor and they are subject to metabolism and/or clearance.
38. The presence of hydroxyl groups on the aromatic ring of SABAs (e.g., in albuterol, terbutaline) is critical for:
- A. Only increasing lipophilicity.
- B. Forming key hydrogen bonds with amino acid residues in the β2-receptor binding site.
- C. Resistance to all forms of metabolism.
- D. Making the molecule highly acidic.
Answer: B. Forming key hydrogen bonds with amino acid residues in the β2-receptor binding site.
39. Modification of the α-carbon of the ethanolamine side chain (e.g., adding a methyl group) in some beta-agonists can:
- A. Always decrease potency.
- B. Potentially increase duration of action by sterically hindering MAO metabolism if the N-substituent is small, and can also influence selectivity.
- C. Eliminate all beta-2 activity.
- D. Convert the agonist to an antagonist.
Answer: B. Potentially increase duration of action by sterically hindering MAO metabolism if the N-substituent is small, and can also influence selectivity. (However, for SABAs like albuterol with large N-substituents, MAO is less of an issue).
40. The development of levalbuterol from racemic albuterol is an example of which medicinal chemistry strategy?
- A. Prodrug design
- B. Isomeric drug development (chiral switch)
- C. Bioisosteric replacement
- D. Ring expansion
Answer: B. Isomeric drug development (chiral switch)
41. The pKa of the amine group in SABAs like albuterol is typically around 9-10. This means at physiological pH (~7.4), a significant portion exists in the _________ form, which is important for receptor interaction.
- A. Deprotonated (free base)
- B. Protonated (cationic)
- C. Zwitterionic
- D. Oxidized
Answer: B. Protonated (cationic)
42. Which structural feature is common to epinephrine, isoproterenol, albuterol, and terbutaline, forming the backbone for beta-receptor interaction?
- A. A steroid nucleus
- B. An arylethanolamine moiety
- C. A dihydropyridine ring
- D. A sulfonamide group
Answer: B. An arylethanolamine moiety
43. The main reason SABAs are preferred for “quick relief” of bronchospasm over LABAs is their:
- A. Greater anti-inflammatory activity.
- B. More rapid onset of bronchodilation.
- C. Longer duration of action allowing for less frequent dosing.
- D. Lower incidence of side effects.
Answer: B. More rapid onset of action.
44. From a medicinal chemistry perspective, what makes isoproterenol (a catecholamine) more susceptible to COMT than albuterol (a saligenin derivative)?
- A. Isoproterenol has a larger N-alkyl group.
- B. Isoproterenol possesses the intact 3,4-dihydroxybenzene (catechol) moiety which is a substrate for COMT.
- C. Albuterol is a prodrug.
- D. Isoproterenol is less water-soluble.
Answer: B. Isoproterenol possesses the intact 3,4-dihydroxybenzene (catechol) moiety which is a substrate for COMT.
45. The chemical stability of SABA solutions for nebulization or in MDIs is important. Factors that can degrade them include:
- A. Only freezing temperatures
- B. Exposure to light, oxygen (oxidation), or incompatible excipients
- C. Only acidic pH
- D. They are extremely stable under all conditions.
Answer: B. Exposure to light, oxygen (oxidation), or incompatible excipients
46. If the ethanolamine -OH group in a SABA is esterified, it would likely create a:
- A. More potent direct agonist
- B. Prodrug that requires hydrolysis to release the active alcohol
- C. Compound with no beta-2 activity
- D. Beta-blocker
Answer: B. Prodrug that requires hydrolysis to release the active alcohol
47. The “ethanolamine” part of the SABA structure is critical. If the -CH2-NH-R part is significantly altered (e.g., replaced by a non-basic group), what would be the expected impact on β2 agonism?
- A. Increased potency
- B. Loss or significant reduction of agonist activity due to altered receptor binding
- C. Conversion to a LABA
- D. No significant impact
Answer: B. Loss or significant reduction of agonist activity due to altered receptor binding
48. The difference in the aromatic ring between metaproterenol (3,5-dihydroxy) and terbutaline (3,5-dihydroxy) is:
- A. Metaproterenol has an N-isopropyl group; terbutaline has an N-tert-butyl group. This is an N-substituent difference, not aromatic ring.
- B. They have the same resorcinol aromatic ring system.
- C. Metaproterenol has a saligenin ring.
- D. Terbutaline has a catechol ring.
Answer: B. They have the same resorcinol aromatic ring system. (The main difference is the N-alkyl group: isopropyl for metaproterenol, t-butyl for terbutaline, which affects selectivity/potency).
49. SAR studies showed that for beta-agonists, optimal interaction with the receptor involves specific hydrogen bonds with the aromatic hydroxyls and the β-hydroxyl. The aromatic ring itself engages in what type of interaction?
- A. Only ionic bonding
- B. Van der Waals or hydrophobic interactions (and potentially pi-stacking)
- C. Covalent bonding
- D. Only metal chelation
Answer: B. Van der Waals or hydrophobic interactions (and potentially pi-stacking)
50. The development of SABAs with modifications to the catechol ring (like albuterol, terbutaline) was a key medicinal chemistry achievement because it primarily addressed the problem of:
- A. Poor patient adherence
- B. High cost of synthesis
- C. Rapid metabolic inactivation by COMT and lack of β2 selectivity of older catecholamine bronchodilators
- D. Insufficient bronchodilator potency
Answer: C. Rapid metabolic inactivation by COMT and lack of β2 selectivity of older catecholamine bronchodilators