Long-acting beta2-agonists (LABAs) are crucial controller medications in the management of persistent asthma (when used in combination with inhaled corticosteroids) and Chronic Obstructive Pulmonary Disease (COPD). Their extended duration of bronchodilation, compared to short-acting beta2-agonists (SABAs), is a direct result of specific structural modifications and physicochemical properties that influence their interaction with the β2-adrenergic receptor and their retention within the airways. For PharmD students, a detailed understanding of the medicinal chemistry of LABAs—including their core structures, structure-activity relationships (SAR) dictating prolonged action, mechanisms of receptor interaction, and metabolic pathways—is vital for appreciating their therapeutic benefits and limitations. This MCQ quiz will explore the key medicinal chemistry aspects of these important respiratory medications.
1. Long-Acting Beta2-Agonists (LABAs) share a common pharmacophore with SABAs, which is typically a(n):
- A. Steroid nucleus
- B. Phenylethanolamine or arylethanolamine structure
- C. Thienopyridine ring
- D. Benzothiazepine structure
Answer: B. Phenylethanolamine or arylethanolamine structure
2. The primary medicinal chemistry strategy for achieving a long duration of action in LABAs like salmeterol involves:
- A. Making the molecule extremely water-soluble for slow absorption.
- B. Incorporating a long, lipophilic N-alkyl substituent that anchors the molecule to an “exosite” near the β2-receptor or within the cell membrane.
- C. Designing them as prodrugs that are very slowly activated.
- D. Ensuring they are resistant to all forms of metabolism.
Answer: B. Incorporating a long, lipophilic N-alkyl substituent that anchors the molecule to an “exosite” near the β2-receptor or within the cell membrane.
3. Salmeterol’s long aliphatic chain, terminating in a phenyl group, is thought to bind to which site on or near the β2-adrenergic receptor to prolong its action?
- A. The orthosteric binding site for the catecholamine head group
- B. An exosite or lipid microdomain adjacent to the active site of the receptor
- C. Intracellularly, to the G-protein
- D. Directly to adenylyl cyclase
Answer: B. An exosite or lipid microdomain adjacent to the active site of the receptor
4. Formoterol, another LABA, achieves its long duration of action partly due to its:
- A. Irreversible binding to the β2-receptor.
- B. Moderate lipophilicity, allowing it to partition into the cell membrane lipid bilayer, forming a depot from which it can re-engage the receptor.
- C. Conversion to multiple, even longer-acting metabolites.
- D. Resistance to all enzymatic degradation.
Answer: B. Moderate lipophilicity, allowing it to partition into the cell membrane lipid bilayer, forming a depot from which it can re-engage the receptor.
5. Arformoterol is the therapeutically active single enantiomer of formoterol. Specifically, it is the:
- A. (S,S)-enantiomer
- B. (R,R)-enantiomer
- C. (R,S)-enantiomer
- D. (S,R)-enantiomer
Answer: B. (R,R)-enantiomer
6. Indacaterol, olodaterol, and vilanterol are classified as “ultra-LABAs” due to their:
- A. Extremely short onset of action (seconds).
- B. Once-daily dosing frequency, resulting from very long duration of action (≥24 hours).
- C. Exclusively oral route of administration.
- D. Ability to also block muscarinic receptors.
Answer: B. Once-daily dosing frequency, resulting from very long duration of action (≥24 hours).
7. The chemical structure of indacaterol, an ultra-LABA, includes a(n) _______ moiety attached to a hydroxyaminoalkyl chain.
- A. Quinolinone
- B. Indane (specifically a carbostyril derivative with an indane portion) or a similar lipophilic group
- C. Thiophene
- D. Steroid
Answer: B. Indane (specifically a carbostyril derivative with an indane portion) or a similar lipophilic group (Indacaterol is an indane derivative, specifically (R)-5-[2-(5,6-diethyl-2,3-dihydro-1H-inden-2-ylamino)-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one). More precise options for clarity or simplification if indane is too specific: 7. The chemical structure of indacaterol, an ultra-LABA, features a large, lipophilic group incorporating which heterocyclic system that contributes to its prolonged action?
- A. A simple benzene ring
- B. A quinolinone moiety combined with an indane-like structure
- C. A thiazole ring
- D. A furan ring
Answer: B. A quinolinone moiety combined with an indane-like structure
8. Vilanterol, used in combination inhalers for once-daily administration, achieves its long duration of action through structural features that promote:
- A. Rapid metabolism to an inactive compound.
- B. High receptor affinity and slow dissociation from the β2-receptor, along with partitioning into cell membranes.
- C. Irreversible covalent binding to the receptor.
- D. Conversion to a short-acting agonist.
Answer: B. High receptor affinity and slow dissociation from the β2-receptor, along with partitioning into cell membranes.
9. Similar to SABAs, the N-alkyl substituent in LABAs is crucial for β2-selectivity. These substituents in LABAs are generally:
- A. Very small (e.g., methyl group).
- B. Large and often lipophilic.
- C. Acidic in nature.
- D. Easily removed by metabolic N-dealkylation to form SABAs.
Answer: B. Large and often lipophilic.
10. The saligenin (3-hydroxymethyl-4-hydroxybenzene) or formamide (-NHCHO group with a 3-OH) moiety on the aromatic ring of some LABAs (e.g., salmeterol, formoterol) serves to:
- A. Increase susceptibility to COMT metabolism.
- B. Provide essential hydrogen bonding interactions with the β2-receptor and confer resistance to COMT.
- C. Make the molecule extremely water-soluble.
- D. Convert the drug into a beta-blocker.
Answer: B. Provide essential hydrogen bonding interactions with the β2-receptor and confer resistance to COMT.
11. Formoterol possesses two chiral centers. The clinically used formoterol is often a racemic mixture of (R,R)- and (S,S)-enantiomers. The (R,R)-enantiomer (arformoterol) is:
- A. Inactive.
- B. The more potent β2-agonist.
- C. Responsible for most side effects.
- D. A β1-selective agonist.
Answer: B. The more potent β2-agonist.
12. The primary metabolic pathways for formoterol include:
- A. Extensive N-dealkylation only.
- B. Direct glucuronidation of the parent drug and O-demethylation followed by glucuronidation.
- C. Hydrolysis of an ester bond.
- D. Complete resistance to metabolism.
Answer: B. Direct glucuronidation of the parent drug and O-demethylation followed by glucuronidation.
13. Salmeterol’s metabolism primarily involves:
- A. Renal excretion as unchanged drug.
- B. Extensive aliphatic hydroxylation of its long N-alkyl side chain by CYP3A4.
- C. O-methylation by COMT.
- D. N-acetylation.
Answer: B. Extensive aliphatic hydroxylation of its long N-alkyl side chain by CYP3A4.
14. The high lipophilicity of the N-substituent in salmeterol is a key factor for its “anchoring” mechanism. This lipophilicity also leads to:
- A. High water solubility.
- B. A tendency for the molecule to partition into and slowly diffuse within the cell membrane.
- C. Rapid clearance from the lungs.
- D. Primarily renal excretion.
Answer: B. A tendency for the molecule to partition into and slowly diffuse within the cell membrane.
15. The “formamide” group (-NH-CHO) in formoterol (at the 3′-position of the aromatic ring) replaces a hydroxyl group compared to traditional catechols or resorcinols. This modification:
- A. Makes it highly susceptible to COMT.
- B. Maintains receptor interaction capability similar to a hydroxyl group while potentially influencing metabolism and selectivity.
- C. Converts the molecule into an antagonist.
- D. Decreases its lipophilicity.
Answer: B. Maintains receptor interaction capability similar to a hydroxyl group while potentially influencing metabolism and selectivity.
16. Vilanterol is structurally characterized by a long N-substituent containing a benzodioxanyl moiety. This complex, lipophilic side chain is designed to:
- A. Ensure rapid onset of action only.
- B. Provide a very long duration of action (24 hours) suitable for once-daily dosing, through strong receptor binding and membrane partitioning.
- C. Be easily metabolized by plasma esterases.
- D. Increase water solubility for IV formulation.
Answer: B. Provide a very long duration of action (24 hours) suitable for once-daily dosing, through strong receptor binding and membrane partitioning.
17. From a medicinal chemistry standpoint, what differentiates an “ultra-LABA” like indacaterol from a traditional LABA like salmeterol?
- A. Ultra-LABAs are always peptides.
- B. Ultra-LABAs generally have even longer durations of action (≥24 hours) allowing for true once-daily dosing, often through a combination of high receptor affinity, slow dissociation, and favorable membrane interactions.
- C. Ultra-LABAs are less selective for β2-receptors.
- D. Ultra-LABAs are prodrugs, while LABAs are not.
Answer: B. Ultra-LABAs generally have even longer durations of action (≥24 hours) allowing for true once-daily dosing, often through a combination of high receptor affinity, slow dissociation, and favorable membrane interactions.
18. The β-hydroxyl group on the ethanolamine side chain of LABAs, like SABAs, must possess which specific stereochemistry for optimal agonist activity?
- A. (S)-configuration
- B. (R)-configuration
- C. A racemic mixture is always required.
- D. The stereochemistry of this group is irrelevant for LABAs.
Answer: B. (R)-configuration
19. The basic amine group in LABAs is essential for forming an ionic bond with an acidic amino acid residue (e.g., Aspartate) in the β2-receptor. At physiological pH, this amine is mostly:
- A. Non-ionized and neutral
- B. Protonated and cationic
- C. Deprotonated and anionic
- D. Oxidized
Answer: B. Protonated and cationic
20. Olodaterol, another ultra-LABA, has a chemical structure that includes a carbostyril (quinolinone) moiety and a substituted N-alkyl chain. These features contribute to its:
- A. Short duration of action.
- B. High intrinsic efficacy and long residence time at the β2-receptor.
- C. Primary action as a beta-1 agonist.
- D. Need for metabolic activation by COMT.
Answer: B. High intrinsic efficacy and long residence time at the β2-receptor.
21. The medicinal chemistry rationale for combining LABAs with Inhaled Corticosteroids (ICS) in asthma treatment is primarily pharmacological, but LABA structures must be compatible with:
- A. Oral administration only.
- B. Formulation in combination inhaler devices (MDIs or DPIs) with ICS.
- C. Rapid systemic absorption and distribution.
- D. Conversion to corticosteroids in vivo.
Answer: B. Formulation in combination inhaler devices (MDIs or DPIs) with ICS.
22. Compared to SABAs, the increased lipophilicity generally seen in LABAs (especially in their N-substituents) contributes to:
- A. Decreased membrane partitioning and shorter duration of action.
- B. Increased membrane partitioning, potentially leading to a depot effect and longer duration of action, and higher protein binding.
- C. Enhanced renal excretion.
- D. Increased susceptibility to COMT.
Answer: B. Increased membrane partitioning, potentially leading to a depot effect and longer duration of action, and higher protein binding.
23. The development of arformoterol as a single (R,R)-enantiomer product of formoterol was driven by the idea that:
- A. The (S,S)-enantiomer is more potent.
- B. The (R,R)-enantiomer is solely responsible for the desired β2-agonist activity, and removing the other enantiomer might reduce potential for off-target effects or differential metabolism.
- C. Racemic formoterol is poorly absorbed.
- D. The (S,S)-enantiomer is a potent beta-blocker.
Answer: B. The (R,R)-enantiomer is solely responsible for the desired β2-agonist activity, and removing the other enantiomer might reduce potential for off-target effects or differential metabolism.
24. What is the primary structural difference in the aromatic ring system between salmeterol and formoterol?
- A. Salmeterol has a catechol ring; formoterol has a resorcinol ring.
- B. Salmeterol has a saligenin-like structure (phenyl with ether-linked side chain); formoterol has a 3-formamido-4-hydroxyphenyl group.
- C. Both have identical aromatic systems.
- D. Salmeterol has a pyridine ring; formoterol has a benzene ring.
Answer: B. Salmeterol has a saligenin-like structure (phenyl with ether-linked side chain); formoterol has a 3-formamido-4-hydroxyphenyl group. (Salmeterol’s aromatic is more complex than a simple saligenin, but the concept is distinct from formoterol’s unique formamide group).
25. The prolonged duration of action of salmeterol, despite its N-alkyl chain being slowly metabolized, is best explained by the “exosite” or “anchoring” hypothesis, where the lipophilic tail:
- A. Causes irreversible covalent binding to the β2-receptor.
- B. Binds to a specific accessory site near the β2-receptor, allowing the active head group to repeatedly engage and disengage from the orthosteric site.
- C. Is slowly converted to multiple active SABA molecules.
- D. Is rapidly excreted unchanged via the lungs.
Answer: B. Binds to a specific accessory site near the β2-receptor, allowing the active head group to repeatedly engage and disengage from the orthosteric site.
26. The presence of a formamide group (-NHCHO) in formoterol’s aromatic ring system contributes to its:
- A. High susceptibility to COMT.
- B. Ability to form hydrogen bonds with the receptor and maintain good intrinsic efficacy, while being different from a catechol.
- C. Conversion to a SABA.
- D. Alpha-1 adrenergic agonism.
Answer: B. Ability to form hydrogen bonds with the receptor and maintain good intrinsic efficacy, while being different from a catechol.
27. Medicinal chemistry strategies for ultra-LABAs like vilanterol often focus on optimizing multiple parameters simultaneously, including:
- A. Only increasing lipophilicity.
- B. High receptor affinity, slow dissociation kinetics (long receptor residence time), and appropriate physicochemical properties for inhaled delivery and once-daily action.
- C. Rapid systemic absorption and slow metabolism.
- D. Ensuring the molecule is a potent beta-1 agonist.
Answer: B. High receptor affinity, slow dissociation kinetics (long receptor residence time), and appropriate physicochemical properties for inhaled delivery and once-daily action.
28. The terminal phenyl group in salmeterol’s long N-alkyl chain is critical for:
- A. The molecule’s water solubility.
- B. Its interaction with the lipophilic exosite, providing the anchoring effect.
- C. Its susceptibility to COMT.
- D. Its direct binding to the orthosteric site of the β2-receptor.
Answer: B. Its interaction with the lipophilic exosite, providing the anchoring effect.
29. From a medicinal chemistry viewpoint, the key challenge in designing LABAs that are safe for asthma when used with ICS is to ensure:
- A. They also have potent anti-inflammatory activity themselves.
- B. Their bronchodilator effect does not mask underlying inflammation if ICS is not used concurrently (though this is more a pharmacology/clinical use point, structure influences this).
- C. Their structure is highly resistant to any metabolism.
- D. They are rapidly absorbed systemically to provide widespread effects.
Rephrasing to focus on structural design for safety/efficacy in combination: 29. From a medicinal chemistry viewpoint, designing LABAs for combination products with ICS requires ensuring their physicochemical properties (e.g., lipophilicity, particle size) are compatible for:
- A. Oral co-administration.
- B. Co-formulation in an inhalation device and similar lung deposition profiles.
- C. Chemical reaction with the ICS to form a new active entity.
- D. Rapid systemic clearance only.
Answer: B. Co-formulation in an inhalation device and similar lung deposition profiles.
30. How does the medicinal chemistry of formoterol, with its moderate lipophilicity, contribute to its relatively rapid onset of action compared to salmeterol, despite both being LABAs?
- A. Formoterol is a more potent direct activator of adenylyl cyclase.
- B. Formoterol can directly access the β2-receptor from the aqueous phase more readily, while also partitioning into the membrane, allowing for both quick and sustained action. Salmeterol’s anchoring takes more time.
- C. Formoterol is administered at much higher doses.
- D. Salmeterol is a prodrug, while formoterol is not.
Answer: B. Formoterol can directly access the β2-receptor from the aqueous phase more readily, while also partitioning into the membrane, allowing for both quick and sustained action. Salmeterol’s anchoring takes more time.
31. The hydrogen bonding interactions between the hydroxyl groups (aromatic and β-OH) of LABAs and specific amino acid residues (e.g., serines, aspartate) in the β2-receptor are crucial for:
- A. Only the molecule’s overall shape.
- B. Receptor binding affinity and activation (agonist efficacy).
- C. Resistance to COMT.
- D. Lipophilicity.
Answer: B. Receptor binding affinity and activation (agonist efficacy).
32. Which structural feature is common to salmeterol, formoterol, and albuterol, and is essential for interacting with the β2-receptor active site?
- A. A long, lipophilic N-alkyl chain
- B. The (R)-configured β-hydroxyl group on the ethanolamine side chain
- C. A formamide group on the aromatic ring
- D. An indane moiety
Answer: B. The (R)-configured β-hydroxyl group on the ethanolamine side chain
33. The choice of salt form for an inhaled LABA (e.g., xinafoate for salmeterol, fumarate for formoterol) is primarily to:
- A. Alter its mechanism of action.
- B. Improve its physicochemical properties for formulation, such as stability and solubility.
- C. Ensure it only acts locally in the lungs.
- D. Convert it into a prodrug.
Answer: B. Improve its physicochemical properties for formulation, such as stability and solubility.
34. The design of ultra-LABAs like indacaterol involved creating molecules with very high intrinsic efficacy and/or:
- A. Very low receptor affinity.
- B. Very slow dissociation rates from the β2-receptor, contributing to their prolonged duration of action.
- C. Primary action on β1-receptors.
- D. Rapid degradation in the airways.
Answer: B. Very slow dissociation rates from the β2-receptor, contributing to their prolonged duration of action.
35. What structural modification strategy used in SABAs to confer COMT resistance is also employed in LABAs like salmeterol and formoterol?
- A. N-dealkylation
- B. Modification of the catechol ring system (e.g., to saligenin or formamide derivatives)
- C. Esterification of the β-hydroxyl group
- D. Introduction of multiple fluorine atoms
Answer: B. Modification of the catechol ring system (e.g., to saligenin or formamide derivatives)
36. The increased lipophilicity of LABAs compared to many SABAs contributes to their longer duration of action by:
- A. Decreasing their affinity for the β2 receptor.
- B. Enhancing their partitioning into the lipid bilayer of cell membranes, creating a local depot.
- C. Facilitating rapid excretion via the kidneys.
- D. Making them more susceptible to COMT.
Answer: B. Enhancing their partitioning into the lipid bilayer of cell membranes, creating a local depot.
37. Arformoterol is the (R,R)-enantiomer of formoterol. The (S,S)-enantiomer of formoterol is:
- A. More potent and selective for β2 receptors.
- B. Significantly less active as a β2-agonist.
- C. A potent beta-blocker.
- D. Responsible for the rapid onset of action.
Answer: B. Significantly less active as a β2-agonist.
38. The chemical stability of LABAs in inhaler formulations is critical. They can be susceptible to:
- A. Only hydrolysis
- B. Oxidation, light degradation, or interaction with excipients if not properly formulated
- C. Spontaneous conversion to SABAs
- D. Only freezing
Answer: B. Oxidation, light degradation, or interaction with excipients if not properly formulated
39. The large, complex N-substituents in ultra-LABAs like vilanterol and olodaterol are primarily designed to:
- A. Decrease β2-selectivity.
- B. Optimize interactions with specific regions of the β2-receptor to achieve high affinity and very long receptor residence time.
- C. Ensure rapid systemic absorption.
- D. Act as a substrate for COMT.
Answer: B. Optimize interactions with specific regions of the β2-receptor to achieve high affinity and very long receptor residence time.
40. From a medicinal chemistry perspective, the transition from SABAs to LABAs and then to ultra-LABAs represents an evolution in designing molecules with:
- A. Decreasing β2-selectivity.
- B. Progressively longer durations of action, allowing for less frequent dosing.
- C. Increased systemic side effects.
- D. Simpler chemical structures.
Answer: B. Progressively longer durations of action, allowing for less frequent dosing.
41. The “phenylalkoxyalkyl” N-substituent of salmeterol is unique. The ether linkage within this long chain provides some flexibility, while the overall chain length and terminal phenyl group are key for:
- A. Rapid onset of action.
- B. The exosite anchoring mechanism and prolonged duration of action.
- C. High water solubility.
- D. Resistance to all CYP450 metabolism.
Answer: B. The exosite anchoring mechanism and prolonged duration of action.
42. The primary metabolic route for indacaterol involves:
- A. Hydrolysis by esterases
- B. Oxidation (e.g., hydroxylation) followed by glucuronidation
- C. N-acetylation
- D. Renal excretion as unchanged drug primarily
Answer: B. Oxidation (e.g., hydroxylation) followed by glucuronidation
43. The development of LABAs often involves optimizing the balance between lipophilicity (for membrane partitioning and duration) and sufficient aqueous solubility for:
- A. Oral tablet formulation.
- B. Effective formulation and delivery via inhalation devices (MDI/DPI).
- C. Intravenous administration.
- D. Transdermal patch delivery.
Answer: B. Effective formulation and delivery via inhalation devices (MDI/DPI).
44. The presence of the β-hydroxyl group in LABAs is crucial. If this group were oxidized to a ketone, the molecule would likely:
- A. Become a more potent β2-agonist.
- B. Lose significant β2-agonist activity.
- C. Gain α1-agonist activity.
- D. Become a LABA prodrug.
Answer: B. Lose significant β2-agonist activity.
45. What is the significance of the N-(1-methyl-2-(4-methoxyphenyl)ethyl) group in formoterol’s structure?
- A. It makes formoterol a potent alpha-agonist.
- B. It confers moderate lipophilicity, contributing to its long duration of action (membrane depot) and rapid onset.
- C. It is readily cleaved to release a SABA.
- D. It ensures complete resistance to metabolism.
Answer: B. It confers moderate lipophilicity, contributing to its long duration of action (membrane depot) and rapid onset.
46. The selection of specific counter-ions (e.g., xinafoate for salmeterol, fumarate for formoterol) for LABA salts can influence:
- A. The drug’s mechanism of action at the receptor.
- B. The drug’s physicochemical properties such as crystallinity, stability, and dissolution rate in formulations.
- C. The drug’s selectivity for β2 over β1 receptors.
- D. The drug’s color.
Answer: B. The drug’s physicochemical properties such as crystallinity, stability, and dissolution rate in formulations.
47. The key SAR feature that differentiates LABAs from SABAs regarding duration of action is primarily related to the:
- A. Nature of the aromatic ring hydroxyl groups.
- B. Stereochemistry of the β-hydroxyl group.
- C. Structure and properties (e.g., length, lipophilicity) of the N-alkyl substituent.
- D. Presence of an α-carbon substituent.
Answer: C. Structure and properties (e.g., length, lipophilicity) of the N-alkyl substituent.
48. Vilanterol trifenatate is the salt form of vilanterol. The trifenatate (triphenylacetate) counterion is chosen for its properties that are suitable for:
- A. Intravenous administration only.
- B. Co-formulation in dry powder inhalers (DPIs) with other agents like fluticasone furoate or umeclidinium.
- C. Rapid oral absorption.
- D. Transdermal delivery.
Answer: B. Co-formulation in dry powder inhalers (DPIs) with other agents like fluticasone furoate or umeclidinium.
49. Medicinal chemists have designed ultra-LABAs like olodaterol with a focus on high intrinsic efficacy at the β2 receptor. Intrinsic efficacy refers to the ability of the drug to:
- A. Bind to the receptor with high affinity.
- B. Activate the receptor and elicit a maximal response once bound.
- C. Resist metabolic degradation.
- D. Be absorbed rapidly from the lungs.
Answer: B. Activate the receptor and elicit a maximal response once bound.
50. The ongoing development in the medicinal chemistry of beta2-agonists, from SABAs to LABAs to ultra-LABAs, has been driven by the therapeutic need for:
- A. Increased systemic side effects.
- B. More convenient dosing regimens (e.g., once-daily), sustained bronchodilation, and suitability for combination therapies.
- C. Drugs that only work for asthma and not COPD.
- D. Lower potency to reduce cost.
Answer: B. More convenient dosing regimens (e.g., once-daily), sustained bronchodilation, and suitability for combination therapies.