SAR of sympathomimetic agents MCQs With Answer

The Structure-Activity Relationship (SAR) of sympathomimetic agents is essential for B. Pharm students to understand how chemical changes affect adrenergic receptor activity, selectivity, metabolism, and pharmacokinetics. This concise introduction covers core concepts: the phenylethylamine backbone, importance of catechol hydroxyls (3,4-positions), beta-hydroxylation, N-substitution effects on alpha/beta selectivity, and metabolic vulnerability to COMT and MAO. Grasping these SAR principles helps predict drug potency, oral bioavailability, receptor preference (alpha1, alpha2, beta1, beta2), and clinical use of agents like epinephrine, phenylephrine, salbutamol, and amphetamine. Clear SAR knowledge also guides medicinal chemistry optimization for safer, more effective sympathomimetics. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. Which structural feature is most associated with high affinity for beta-adrenergic receptors in sympathomimetic agents?

• A catechol (3,4-dihydroxy) phenyl ring with a beta-hydroxylated side chain
• A phenyl ring lacking hydroxyl groups and no beta-hydroxyl
• A quaternary ammonium with bulky N-alkyl groups
• A para-nitro substitution on the aromatic ring

Correct Answer: A catechol (3,4-dihydroxy) phenyl ring with a beta-hydroxylated side chain

Q2. Replacement of the N-H hydrogen in phenylethylamine by a bulky tert-butyl group typically results in:

• Increased alpha-1 selectivity
• Increased beta-2 selectivity
• Loss of all adrenergic activity
• Increased susceptibility to COMT

Correct Answer: Increased beta-2 selectivity

Q3. Which modification increases resistance to COMT metabolism in catecholamines?

• Presence of both 3,4-dihydroxy (catechol) groups
• Removal of one hydroxyl (making mono-hydroxy phenol)
• Addition of a para-methoxy group while keeping 3-OH
• Alpha-hydroxylation on the side chain

Correct Answer: Removal of one hydroxyl (making mono-hydroxy phenol)

Q4. Alpha-methyl substitution on the side chain (as in amphetamine) primarily results in:

• Increased direct alpha-1 agonism and rapid COMT metabolism
• Reduced penetration into CNS and loss of indirect action
• Increased resistance to MAO and enhanced indirect sympathomimetic CNS activity
• Greater susceptibility to hydrolysis by esterases

Correct Answer: Increased resistance to MAO and enhanced indirect sympathomimetic CNS activity

Q5. Which structural feature favors indirect sympathomimetic action (release of endogenous norepinephrine)?

• Beta-hydroxyl group with a catechol ring
• Amphetamine-like alpha-methylated phenethylamine core
• Quaternary ammonium preventing membrane crossing
• Large polar substituents on the aromatic ring

Correct Answer: Amphetamine-like alpha-methylated phenethylamine core

Q6. Which of the following agents is an example of a direct-acting beta agonist due to catechol structure and N-isopropyl substitution?

• Phenylephrine
• Isoproterenol
• Tyramine
• Ephedrine

Correct Answer: Isoproterenol

Q7. Presence of a beta-hydroxyl group (as in epinephrine) typically causes:

• Loss of receptor activity
• Conversion to primarily indirect action
• Increased direct agonist potency at adrenergic receptors
• Increased metabolic clearance by esterases

Correct Answer: Increased direct agonist potency at adrenergic receptors

Q8. Which substitution pattern on the aromatic ring is characteristic of catecholamines like norepinephrine?

• Ortho, para-dihydroxy (2,4)
• Meta, para-dihydroxy (3,4)
• Mono-hydroxy at para position only (4-OH)
• No hydroxyl groups

Correct Answer: Meta, para-dihydroxy (3,4)

Q9. Quaternary ammonium derivatives of sympathomimetics are typically:

• Highly able to cross the blood–brain barrier
• Poorly orally bioavailable and unable to cross membranes readily
• More resistant to COMT than tertiary amines
• Preferentially beta-2 selective

Correct Answer: Poorly orally bioavailable and unable to cross membranes readily

Q10. Which chemical change generally improves oral bioavailability of a sympathomimetic agent?

• Introducing 3,4-dihydroxy groups on the ring
• Converting a catechol to a mono-hydroxy or methoxy derivative
• Adding multiple polar charged groups
• Introducing an unprotected primary amine

Correct Answer: Converting a catechol to a mono-hydroxy or methoxy derivative

Q11. Salbutamol (albuterol) achieves beta-2 selectivity mainly because of:

• A catechol ring with 3,4-dihydroxy groups
• A bulky tertiary butyl group on the amino nitrogen
• An aromatic nitro substituent at the para position
• A quaternary ammonium center

Correct Answer: A bulky tertiary butyl group on the amino nitrogen

Q12. Which modification tends to increase alpha-adrenergic receptor activity over beta activity?

• Bulky N-alkyl substituents (t-butyl)
• Small N-methyl substitution
• Removal of beta-hydroxyl group
• Introduction of catechol 3,4-OH

Correct Answer: Small N-methyl substitution

Q13. Why are catecholamines like epinephrine poorly effective orally?

• They are rapidly metabolized by COMT and MAO
• They are too lipophilic and sequestered in fat
• They are stable but poorly absorbed from gut
• They form insoluble salts in stomach

Correct Answer: They are rapidly metabolized by COMT and MAO

Q14. Which structural feature is most associated with central nervous system stimulation by sympathomimetics?

• Quaternary ammonium that restricts CNS entry
• Greater lipophilicity and lack of polar catechol groups
• Presence of multiple charged groups
• Large glycosylated substituents

Correct Answer: Greater lipophilicity and lack of polar catechol groups

Q15. Phenylephrine is primarily an alpha-1 agonist because it:

• Has a catechol 3,4-dihydroxy ring
• Lacks the 3-hydroxyl, reducing COMT sensitivity and favoring alpha activity
• Contains a bulky t-butyl group at nitrogen
• Is a quaternary ammonium compound

Correct Answer: Lacks the 3-hydroxyl, reducing COMT sensitivity and favoring alpha activity

Q16. Addition of a phenolic 4-hydroxyl group on the ring typically:

• Decreases receptor affinity and potency
• Enhances interaction with adrenergic receptors and increases potency
• Makes the molecule resistant to MAO
• Converts the agent to an antagonist

Correct Answer: Enhances interaction with adrenergic receptors and increases potency

Q17. Which statement about isomerism in sympathomimetics is correct?

• Stereochemistry at the beta-carbon does not affect potency
• Enantiomers often show different potency and receptor selectivity
• All racemic mixtures are inactive
• Only meso forms are active at adrenergic receptors

Correct Answer: Enantiomers often show different potency and receptor selectivity

Q18. Which structural element differentiates ephedrine from amphetamine in terms of mechanism?

• Ephedrine has a beta-hydroxyl group enabling some direct receptor action
• Amphetamine contains a catechol ring making it a potent beta agonist
• Ephedrine is a quaternary ammonium compound
• Amphetamine lacks an aromatic ring

Correct Answer: Ephedrine has a beta-hydroxyl group enabling some direct receptor action

Q19. Converting a primary amine to a tertiary amine in phenethylamines generally:

• Eliminates biological activity entirely
• Alters potency and can change receptor subtype selectivity
• Makes the compound a substrate for COMT
• Prevents absorption from the GI tract

Correct Answer: Alters potency and can change receptor subtype selectivity

Q20. Which modification would be expected to reduce peripheral adrenergic activity but increase central stimulant effects?

• Introduction of a quaternary ammonium group
• Adding polar catechol hydroxyls
• Removing polar hydroxyls to increase lipophilicity
• Converting the amine to an amide

Correct Answer: Removing polar hydroxyls to increase lipophilicity

Q21. Which property of sympathomimetics is directly improved by methylation of the alpha-carbon?

• Faster degradation by MAO
• Increased indirect CNS stimulant action and MAO resistance
• Increased COMT metabolism on the aromatic ring
• Loss of adrenergic receptor binding

Correct Answer: Increased indirect CNS stimulant action and MAO resistance

Q22. A para-substituted bulky aromatic group often leads to:

• Greater alpha-2 receptor selectivity
• Loss of all adrenergic activity
• Enhanced steric hindrance and altered receptor interaction
• Increased susceptibility to MAO

Correct Answer: Enhanced steric hindrance and altered receptor interaction

Q23. Which change would most likely increase duration of action by reducing COMT metabolism?

• Introducing a 3,4-dihydroxy catechol
• Removing one ring hydroxyl or replacing with methoxy
• Adding an alpha-hydroxyl group
• Converting the amine to a quaternary ammonium

Correct Answer: Removing one ring hydroxyl or replacing with methoxy

Q24. Why does isoproterenol have strong beta activity compared to epinephrine on a per-molecule basis?

• Because it lacks a catechol ring entirely
• Because N-isopropyl substitution and catechol ring favor beta receptor interaction
• Because it is a quaternary ammonium compound
• Because it has a para-nitro group enhancing beta selectivity

Correct Answer: Because N-isopropyl substitution and catechol ring favor beta receptor interaction

Q25. A sympathomimetic with a bulky polar group at the aromatic ring will most likely:

• Have enhanced membrane permeability and CNS action
• Show altered receptor binding and possibly reduced potency
• Be a better substrate for COMT
• Act exclusively as an MAO inhibitor

Correct Answer: Show altered receptor binding and possibly reduced potency

Q26. Which structural attribute is critical for direct agonist interaction with adrenergic receptors?

• Presence of a sugar moiety
• Proper spacing between the aromatic ring and the protonated nitrogen
• Conjugated double bonds in the side chain
• Large halogen substituents on the ring

Correct Answer: Proper spacing between the aromatic ring and the protonated nitrogen

Q27. Tyramine is primarily an indirect sympathomimetic because it:

• Is a strong direct agonist at beta-2 receptors
• Releases stored norepinephrine from nerve terminals
• Has a bulky N-tert-butyl group
• Contains a catechol 3,4-dihydroxy motif

Correct Answer: Releases stored norepinephrine from nerve terminals

Q28. Which substitution would you expect to reduce affinity for alpha and beta receptors but increase oral stability?

• Adding 3,4-dihydroxy groups
• Replacing one hydroxyl with a methoxy group
• Adding a small N-methyl group
• Introducing an alpha-hydroxyl group

Correct Answer: Replacing one hydroxyl with a methoxy group

Q29. What is the likely effect of converting a secondary amine into a tertiary amine in a sympathomimetic?

• Complete loss of basicity
• Altered pharmacokinetics and receptor subtype preference
• Increased COMT-mediated metabolism
• Guaranteed increase in alpha-1 potency

Correct Answer: Altered pharmacokinetics and receptor subtype preference

Q30. Which functional group on the side chain enhances interaction with adrenergic receptors and is common in direct-acting catecholamines?

• Alpha-carboxyl group
• Beta-hydroxyl group
• Terminal ester group
• Thiol (-SH) group

Correct Answer: Beta-hydroxyl group

Q31. Which modification of epinephrine analogs is typically used to achieve longer duration of action for therapeutic use?

• Maintaining free catechol dihydroxy groups unchanged
• Alkylation or methylation of ring hydroxyls to resist COMT
• Converting the amine into a quaternary ammonium
• Introducing multiple carboxyl groups

Correct Answer: Alkylation or methylation of ring hydroxyls to resist COMT

Q32. Which property correlates with increased beta-1 cardiac stimulation in sympathomimetics?

• Bulky N-tert-butyl substitution
• Small N-alkyl substituents and catechol ring presence
• Complete loss of aromatic hydroxyls
• Quaternary ammonium center

Correct Answer: Small N-alkyl substituents and catechol ring presence

Q33. A sympathomimetic lacking the beta-hydroxyl but retaining the aromatic ring is more likely to be:

• Primarily indirect-acting and more CNS-penetrant
• Highly selective beta-2 agonist
• Completely inactive at adrenergic receptors
• Subject to rapid metabolism by COMT only

Correct Answer: Primarily indirect-acting and more CNS-penetrant

Q34. Which change would favor peripheral selectivity and reduced CNS side effects?

• Increase lipophilicity and remove ring hydroxyls
• Introduce charged quaternary ammonium or polar groups
• Methylate the alpha-carbon
• Remove all polar substituents

Correct Answer: Introduce charged quaternary ammonium or polar groups

Q35. The presence of a 3,4-dihydroxy aromatic ring primarily contributes to:

• Reduced receptor affinity and increased oral bioavailability
• High potency at adrenergic receptors but rapid COMT metabolism
• Selective muscarinic receptor activation
• Poor aqueous solubility leading to renal excretion

Correct Answer: High potency at adrenergic receptors but rapid COMT metabolism

Q36. Which structural motif differentiates direct-acting alpha-1 agonists like phenylephrine from catecholamines?

• Presence of a catechol 3,4-dihydroxy ring
• Mono-hydroxylated aromatic ring (usually para) and lack of 3-OH
• Alpha-methyl substitution leading to MAO susceptibility
• Quaternary ammonium increasing BBB penetration

Correct Answer: Mono-hydroxylated aromatic ring (usually para) and lack of 3-OH

Q37. Which structural change converts a peripherally acting sympathomimetic to one with greater CNS stimulant effect?

• Adding polar groups to increase water solubility
• Removing polar ring hydroxyls and increasing lipophilicity
• Converting tertiary amine to quaternary ammonium
• Attaching a large carbohydrate chain

Correct Answer: Removing polar ring hydroxyls and increasing lipophilicity

Q38. A drug designed to resist MAO metabolism would likely have which feature?

• Unsubstituted primary amine at the alpha position
• Alpha-methyl substitution adjacent to the amine
• A free catechol ring with no steric hindrance
• Terminal carboxyl group on the side chain

Correct Answer: Alpha-methyl substitution adjacent to the amine

Q39. Which of these is a consequence of adding large lipophilic substituents to the aromatic ring of sympathomimetics?

• Decreased ability to cross membranes
• Altered receptor subtype binding and potential increase in oral absorption
• Increased rate of COMT metabolism
• Complete loss of adrenergic receptor activity

Correct Answer: Altered receptor subtype binding and potential increase in oral absorption

Q40. Pseudoephedrine differs from ephedrine mainly in stereochemistry and is used as a decongestant because it:

• Is a direct potent beta-2 agonist with catechol ring
• Acts primarily by releasing norepinephrine and has some direct alpha activity
• Is a quaternary ammonium that cannot cross membranes
• Has extensive COMT metabolism making it inactive orally

Correct Answer: Acts primarily by releasing norepinephrine and has some direct alpha activity

Q41. Which modification is commonly used to design selective beta-2 agonists for bronchodilation?

• Retention of catechol 3,4-dihydroxy and small N-methyl group
• Bulky N-tert-butyl substitution and appropriate aryl substitutions
• Conversion to a quaternary ammonium salt
• Introduction of a carboxylate ester on the side chain

Correct Answer: Bulky N-tert-butyl substitution and appropriate aryl substitutions

Q42. Which structural aspect tends to reduce peripheral cardiovascular effects while retaining bronchodilation?

• Non-selective catecholamines with small N-alkyl groups
• Beta-2 selective substitution such as bulky N groups and specific aryl modifications
• Increased COMT susceptibility through more hydroxyls
• Quaternary ammonium formation to increase CNS penetration

Correct Answer: Beta-2 selective substitution such as bulky N groups and specific aryl modifications

Q43. Which of the following is true regarding N-methylation of sympathomimetic amines?

• N-methylation always abolishes activity
• N-methylation can increase potency or alter selectivity compared to primary amines
• N-methylation makes the drug a substrate for COMT
• N-methylation converts the compound into an antagonist

Correct Answer: N-methylation can increase potency or alter selectivity compared to primary amines

Q44. How does the presence of a beta-phenyl ring (i.e., extension of aromaticity) generally affect sympathomimetic activity?

• Creates an MAO substrate with high oral bioavailability
• Often decreases activity at classical adrenergic receptors and may redirect pharmacology
• Guaranteed increase in alpha-1 potency
• Converts the molecule into a permanent ion

Correct Answer: Often decreases activity at classical adrenergic receptors and may redirect pharmacology

Q45. Which structural modification is often used to reduce systemic side effects of nasal decongestants?

• Designing highly lipophilic molecules to enhance CNS distribution
• Using less COMT-susceptible mono-hydroxy analogs with limited systemic absorption
• Converting the agent to quaternary ammonium to enhance GI absorption
• Adding alpha-methyl groups to increase CNS stimulant effects

Correct Answer: Using less COMT-susceptible mono-hydroxy analogs with limited systemic absorption

Q46. The pharmacological effect of removing the 4-hydroxyl from a catecholamine typically is to:

• Completely abolish adrenergic receptor binding
• Reduce potency but increase metabolic stability
• Increase COMT metabolism rate
• Convert the drug into a muscarinic agonist

Correct Answer: Reduce potency but increase metabolic stability

Q47. Which structural characteristic would most likely make a sympathomimetic a poor substrate for COMT?

• Having both 3- and 4-hydroxyls free on the aromatic ring
• Having only one phenolic hydroxyl or methoxy in place of one OH
• Having an unsubstituted aromatic ring
• Having a carboxylate group on the aromatic ring

Correct Answer: Having only one phenolic hydroxyl or methoxy in place of one OH

Q48. Which factor most influences whether a sympathomimetic will act more on alpha or beta receptors?

• Number and position of aromatic hydroxyl groups and N-substitution size
• Molecular weight only
• Presence of halogen atoms exclusively
• Whether the drug is crystalline or amorphous

Correct Answer: Number and position of aromatic hydroxyl groups and N-substitution size

Q49. Which of the following structural changes would likely increase selectivity for peripheral alpha receptors over beta receptors?

• Adding bulky N-tert-butyl substitution
• Using small N-alkyl groups and maintaining catechol hydroxyls
• Removing aromatic hydroxyls completely
• Converting the amine into a tertiary butyl quaternary salt

Correct Answer: Using small N-alkyl groups and maintaining catechol hydroxyls

Q50. In medicinal chemistry optimization, what is a common trade-off when modifying a sympathomimetic to increase oral bioavailability?

• Increased receptor potency with no change in metabolism
• Reduced receptor potency or selectivity while improving metabolic stability and absorption
• Elimination of all side effects automatically
• Guaranteed increased beta-2 selectivity

Correct Answer: Reduced receptor potency or selectivity while improving metabolic stability and absorption

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