SAR of parasympathomimetic agents MCQs With Answer

Introduction:

The structure-activity relationship (SAR) of parasympathomimetic agents is a key topic for B. Pharm students preparing for pharmacology and medicinal chemistry exams. This concise guide highlights how features such as a positively charged nitrogen, ester or carbamate groups, beta-substitution, and lipophilicity determine muscarinic vs nicotinic activity, metabolic stability, receptor selectivity, and CNS penetration. Understanding differences between choline esters (e.g., acetylcholine, methacholine, bethanechol, carbachol) and alkaloids (e.g., pilocarpine) helps predict pharmacokinetics, potency, and clinical use. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. Which combination best describes the classical pharmacophore requirements for muscarinic agonists?

• A positively charged nitrogen and a hydrogen-bond acceptor separated by an optimal distance
• An aromatic ring and a carboxylic acid group
• A sulfhydryl group and a bulky hydrophobic tail
• A peroxide linkage and a quaternary phosphate

Correct Answer: A positively charged nitrogen and a hydrogen-bond acceptor separated by an optimal distance

Q2. How does conversion of a tertiary amine to a quaternary ammonium in parasympathomimetics typically affect activity?

• Increases receptor binding but reduces CNS penetration
• Eliminates receptor binding and increases CNS penetration
• Has no effect on receptor binding or CNS penetration
• Always converts agonists into antagonists

Correct Answer: Increases receptor binding but reduces CNS penetration

Q3. Beta-methylation of acetylcholine (as in methacholine) primarily produces which effect?

• Increases muscarinic selectivity over nicotinic receptors
• Makes the compound an acetylcholinesterase activator
• Converts it to a muscarinic antagonist
• Greatly increases lipophilicity and CNS toxicity

Correct Answer: Increases muscarinic selectivity over nicotinic receptors

Q4. Replacing the ester oxygen of acetylcholine with a carbamate group generally results in:

• Increased resistance to acetylcholinesterase hydrolysis
• Complete loss of muscarinic activity
• Formation of a potent nicotinic antagonist
• Immediate conversion into a prodrug requiring activation

Correct Answer: Increased resistance to acetylcholinesterase hydrolysis

Q5. Which parasympathomimetic is a noncholine alkaloid commonly used as an ocular miotic?

• Pilocarpine
• Acetylcholine
• Methacholine
• Carbachol

Correct Answer: Pilocarpine

Q6. Which structural modification is most useful to increase a direct muscarinic agonist’s metabolic stability in plasma?

• Replace the ester linkage with a carbamate
• Add a free carboxyl group to the molecule
• Introduce a labile peroxide bond
• Remove all polar functionalities

Correct Answer: Replace the ester linkage with a carbamate

Q7. What is the typical effect on muscarinic agonist potency when the nitrogen substituents are enlarged beyond methyl groups?

• Potency decreases due to steric hindrance
• Potency always increases linearly
• Potency becomes independent of receptor binding
• It converts the drug into a cholinesterase inhibitor

Correct Answer: Potency decreases due to steric hindrance

Q8. The optimal separation between the cationic nitrogen and the ester oxygen in classical choline esters is equivalent to:

• Two carbon atoms (N–C–C–O spacing)
• Five carbon atoms
• An aromatic bridge
• A direct N–O bond

Correct Answer: Two carbon atoms (N–C–C–O spacing)

Q9. Which agent is typically used in the methacholine challenge test to diagnose bronchial hyperreactivity?

• Methacholine
• Bethanechol
• Pilocarpine
• Atropine

Correct Answer: Methacholine

Q10. Why are quaternary choline esters generally poorly absorbed orally?

• They are permanently charged and highly polar, limiting membrane permeation
• They are converted to toxic radicals in the gut
• They are rapidly absorbed and then excreted unchanged
• They are lipophilic and sequestered in adipose tissue

Correct Answer: They are permanently charged and highly polar, limiting membrane permeation

Q11. Bulky substituents on the alpha-carbon adjacent to the quaternary nitrogen generally cause what effect on muscarinic activity?

• Decrease activity due to steric interference with receptor binding
• Increase activity by enhancing receptor fit
• Convert the compound into a nicotinic agonist
• Have no measurable effect

Correct Answer: Decrease activity due to steric interference with receptor binding

Q12. Which property of pilocarpine explains its ability to produce central effects compared with quaternary choline esters?

• It is a tertiary amine and more lipophilic, allowing CNS penetration
• It contains two quaternary ammonium centers
• It is rapidly hydrolyzed in plasma
• It has a heavy metal atom in the structure

Correct Answer: It is a tertiary amine and more lipophilic, allowing CNS penetration

Q13. Which of the following drugs is a carbamate choline ester known to be resistant to acetylcholinesterase hydrolysis?

• Carbachol
• Acetylcholine
• Methacholine (majorly susceptible)
• Pilocarpine

Correct Answer: Carbachol

Q14. Methacholine differs from acetylcholine by which substitution?

• A methyl group on the beta-carbon
• An additional aromatic ring
• Replacement of the ester with a thioester
• Introduction of a phosphate group

Correct Answer: A methyl group on the beta-carbon

Q15. Which structural change is most associated with increased muscarinic selectivity and reduced nicotinic action?

• Beta-methyl substitution on the ethylene bridge
• Introduction of a long alkyl chain on the nitrogen
• Formation of a disulfide bridge
• Aromatic ring fusion to the choline moiety

Correct Answer: Beta-methyl substitution on the ethylene bridge

Q16. Converting a muscarinic agonist’s ester to a bulky ester (larger acyl group) generally results in:

• Increased resistance to enzymatic hydrolysis
• Faster hydrolysis by acetylcholinesterase
• Conversion into a muscarinic antagonist
• No change in metabolism

Correct Answer: Increased resistance to enzymatic hydrolysis

Q17. Which functional group in choline esters commonly serves as the hydrogen-bond acceptor required for muscarinic receptor binding?

• The ester oxygen
• A free thiol group
• A primary amide nitrogen
• A phenolic OH group

Correct Answer: The ester oxygen

Q18. Replacing the ester oxygen with a sulfur atom (thioester) typically has what effect on muscarinic agonist potency?

• Decreases potency due to poorer hydrogen-bonding and fit
• Greatly increases potency and selectivity
• Converts the compound into an irreversible agonist
• Makes the molecule impermeable to membranes but unchanged in potency

Correct Answer: Decreases potency due to poorer hydrogen-bonding and fit

Q19. Which choline ester is commonly used to stimulate bladder and gastrointestinal smooth muscle postoperatively?

• Bethanechol
• Acetylcholine
• Pilocarpine
• Scopolamine

Correct Answer: Bethanechol

Q20. The oral activity and stability of pilocarpine are primarily due to which SAR feature?

• Noncholine heterocyclic structure and tertiary amine that resists AChE hydrolysis
• Presence of a quaternary ammonium that enhances absorption
• A long polyethylene glycol chain that improves stability
• A phosphate prodrug moiety

Correct Answer: Noncholine heterocyclic structure and tertiary amine that resists AChE hydrolysis

Q21. Increasing bulk on the quaternary nitrogen of a muscarinic agonist beyond small alkyl groups typically:

• Reduces muscarinic activity by steric interference
• Converts the compound to a selective M2 agonist
• Has no influence on receptor interaction
• Enhances passage across the blood–brain barrier

Correct Answer: Reduces muscarinic activity by steric interference

Q22. Between bethanechol and carbachol, which is more muscarinic-selective and why?

• Bethanechol, because beta-methylation increases muscarinic selectivity
• Carbachol, because it is more lipophilic
• Neither; both are exclusively nicotinic agonists
• Carbachol, because it contains an aromatic ring

Correct Answer: Bethanechol, because beta-methylation increases muscarinic selectivity

Q23. Which direct-acting muscarinic agonist is known for producing ocular miosis and is commonly used in glaucoma therapy?

• Pilocarpine
• Bethanechol
• Methacholine
• Neostigmine

Correct Answer: Pilocarpine

Q24. Conformational constraint in drug design for parasympathomimetics aims to:

• Lock the molecule into a bioactive conformation to improve potency and selectivity
• Make the molecule more susceptible to hydrolysis
• Ensure the drug is completely inactive until metabolized
• Reduce binding to the target receptor by increasing flexibility

Correct Answer: Lock the molecule into a bioactive conformation to improve potency and selectivity

Q25. Which structural feature is most responsible for longer duration of action in carbamate muscarinic agonists?

• The carbamate linkage is hydrolyzed more slowly than an ester
• Presence of an aromatic ring that undergoes slow metabolism
• A free aldehyde group that forms adducts
• A labile peroxide bond

Correct Answer: The carbamate linkage is hydrolyzed more slowly than an ester

Q26. Which N-substitution pattern is optimal for classical muscarinic agonist potency?

• Small alkyl groups such as methyl substituents
• Bulky branched alkyl groups like tert-butyl
• Attachment of an aromatic benzyl group
• No nitrogen at all

Correct Answer: Small alkyl groups such as methyl substituents

Q27. Which of the following is a choline ester rather than a natural alkaloid?

• Carbachol
• Pilocarpine
• Arecoline
• Muscarine

Correct Answer: Carbachol

Q28. Which adverse effect is most likely from systemic overdose of a nonselective parasympathomimetic agent?

• Bradycardia and bronchospasm
• Hypertension and tachycardia
• Hyperthermia and dry skin
• Sedation without autonomic signs

Correct Answer: Bradycardia and bronchospasm

Q29. What is the predicted outcome if the cationic nitrogen in a muscarinic agonist is not protonated at physiological pH?

• Loss of agonist activity due to inability to engage ionic receptor site
• Greatly increased agonist potency
• Drug becomes an irreversible enzyme inhibitor
• Conversion into a selective M3 antagonist

Correct Answer: Loss of agonist activity due to inability to engage ionic receptor site

Q30. The characteristic N–C–C–O arrangement in acetylcholine analogs corresponds to what structural feature?

• An ethylene bridge between nitrogen and ester oxygen
• A direct nitrogen–oxygen bond
• A benzyl spacer between the functional groups
• A triple bond between nitrogen and carbon

Correct Answer: An ethylene bridge between nitrogen and ester oxygen

Q31. Why do bulky acyl groups attached to the choline ester generally slow enzymatic hydrolysis?

• Steric hindrance reduces access of acetylcholinesterase to the ester bond
• They increase polarity making the molecule invisible to enzymes
• Bulky acyl groups activate competing enzymes that protect the drug
• They convert the ester into an amide group spontaneously

Correct Answer: Steric hindrance reduces access of acetylcholinesterase to the ester bond

Q32. Which design strategy is commonly used to increase CNS penetration of a muscarinic agonist?

• Convert a quaternary ammonium to a tertiary amine and increase lipophilicity
• Introduce two quaternary ammonium centers
• Add charged sulfate groups to improve brain uptake
• Increase molecular polarity by adding multiple hydroxyls

Correct Answer: Convert a quaternary ammonium to a tertiary amine and increase lipophilicity

Q33. Which example of a muscarinic agonist is preferred clinically for urinary retention due to its selectivity and resistance to AChE?

• Bethanechol
• Acetylcholine
• Pilocarpine
• Nicotine

Correct Answer: Bethanechol

Q34. Which of the following modifications will most likely decrease muscarinic agonist activity?

• Removing the ester oxygen that acts as an H-bond acceptor
• Introducing a beta-methyl group
• Using small N-methyl substituents
• Replacing ester with carbamate to prolong action

Correct Answer: Removing the ester oxygen that acts as an H-bond acceptor

Q35. Alpha-carbon methylation (adjacent to the quaternary nitrogen) typically leads to what effect?

• Decreased activity due to steric clash at the receptor
• Marked increase in muscarinic potency
• Conversion into a cholinesterase activator
• Production of selective nicotinic antagonists

Correct Answer: Decreased activity due to steric clash at the receptor

Q36. Which bioisosteric replacement is frequently used to design AChE-resistant analogs of acetylcholine?

• Replace ester with a carbamate moiety
• Replace ester with a phosphate diester
• Replace choline moiety with a sulfate group
• Replace nitrogen with an oxygen atom

Correct Answer: Replace ester with a carbamate moiety

Q37. Which structural alteration tends to favor nicotinic activity rather than muscarinic activity?

• Absence of a beta-hydroxyl or beta-methyl and a more linear geometry
• Presence of a beta-methyl group and bulky N-methylation
• Conversion to a carbamate with tertiary amine
• Attachment of a bulky aromatic acyl group

Correct Answer: Absence of a beta-hydroxyl or beta-methyl and a more linear geometry

Q38. Lipophilic, noncholine muscarinic agonists are more likely to:

• Cross the blood–brain barrier and show central effects
• Be rapidly hydrolyzed by acetylcholinesterase in plasma
• Have zero affinity for muscarinic receptors
• Act exclusively as peripheral nicotinic antagonists

Correct Answer: Cross the blood–brain barrier and show central effects

Q39. The presence of which moiety in a parasympathomimetic increases resistance to enzymatic degradation and prolongs activity?

• Carbamate linkage
• Simple acetate ester
• Primary alcohol
• Epoxide ring

Correct Answer: Carbamate linkage

Q40. What is the likely pharmacological consequence of replacing an ester oxygen with a methylene (–CH2–) in a choline ester analog?

• Marked loss of muscarinic agonist activity due to loss of H-bond acceptor
• Huge increase in AChE-mediated hydrolysis
• Conversion into a potent AChE substrate
• No effect on receptor interaction

Correct Answer: Marked loss of muscarinic agonist activity due to loss of H-bond acceptor

Q41. Which of the following is a typical clinical use tied to SAR of bethanechol?

• Treatment of postoperative urinary retention due to muscarinic selectivity
• Management of Alzheimer’s disease as a CNS stimulant
• Long-term bronchodilation in asthma
• Systemic neuromuscular blockade during surgery

Correct Answer: Treatment of postoperative urinary retention due to muscarinic selectivity

Q42. In the design of parasympathomimetic drugs, why is retention of a positively charged center important?

• It forms ionic interactions with a negatively charged site on the receptor
• It makes the molecule highly lipophilic for membrane diffusion
• It ensures irreversible binding to the receptor
• It increases susceptibility to oxidative metabolism

Correct Answer: It forms ionic interactions with a negatively charged site on the receptor

Q43. Which property differentiates pilocarpine from choline esters in terms of metabolism?

• Pilocarpine is not a substrate for acetylcholinesterase and is metabolized differently
• Pilocarpine is hydrolyzed faster by acetylcholinesterase than acetylcholine
• Pilocarpine forms covalent bonds with AChE
• Pilocarpine spontaneously decomposes into acetylcholine in vivo

Correct Answer: Pilocarpine is not a substrate for acetylcholinesterase and is metabolized differently

Q44. Replacement of the ester group by an amide in a choline analog typically results in:

• Reduced muscarinic potency due to altered hydrogen-bonding and geometry
• Markedly increased acetylcholinesterase hydrolysis
• Immediate activation to a potent agonist
• No change in pharmacological profile

Correct Answer: Reduced muscarinic potency due to altered hydrogen-bonding and geometry

Q45. Which SAR observation explains why many muscarinic agonists have limited oral bioavailability?

• Permanent positive charge (quaternary ammonium) and rapid enzymatic hydrolysis reduce absorption
• They form insoluble salts in the gut that are not absorbed
• They require carrier-mediated transport present only in the skin
• They are converted into volatile gases in the stomach

Correct Answer: Permanent positive charge (quaternary ammonium) and rapid enzymatic hydrolysis reduce absorption

Q46. Which change is most consistent with designing a muscarinic agonist with prolonged peripheral action but minimal CNS effects?

• Introduce a quaternary ammonium and a carbamate linkage
• Convert nitrogen to tertiary amine and increase lipophilicity
• Add polar neutral groups that increase BBB penetration
• Attach a lipophilic benzyl moiety to cross the BBB

Correct Answer: Introduce a quaternary ammonium and a carbamate linkage

Q47. Which of the following best explains why carbachol can be used topically in the eye?

• Carbachol is resistant to AChE and can produce local muscarinic effects when applied topically
• Carbachol is rapidly absorbed systemically producing generalized effects
• Carbachol is a nicotinic antagonist that relaxes ocular muscles
• Carbachol is converted to pilocarpine in ocular tissues

Correct Answer: Carbachol is resistant to AChE and can produce local muscarinic effects when applied topically

Q48. Which structural modification would most likely increase lipophilicity and aid membrane permeability for a muscarinic agonist?

• Convert a quaternary ammonium to a tertiary amine and add nonpolar substituents
• Add an extra positive charge to the molecule
• Increase the number of free hydroxyl groups
• Attach a charged sulfate group

Correct Answer: Convert a quaternary ammonium to a tertiary amine and add nonpolar substituents

Q49. Which of the following is a reliable SAR strategy to reduce peripheral muscarinic side effects while preserving desired central action?

• Design a tertiary amine with balanced lipophilicity to favor CNS penetration over peripheral exposure
• Make the molecule a permanent quaternary ammonium to increase peripheral action
• Add bulky hydrophilic groups to increase renal clearance immediately
• Remove the cationic center to prevent receptor binding

Correct Answer: Design a tertiary amine with balanced lipophilicity to favor CNS penetration over peripheral exposure

Q50. Which practical SAR lesson explains why clinicians choose bethanechol instead of acetylcholine for treating urinary retention?

• Bethanechol has muscarinic selectivity (beta-methyl) and resistance to acetylcholinesterase, providing longer peripheral action
• Acetylcholine is more selective for M3 receptors and therefore not useful
• Bethanechol is a nicotinic antagonist that stimulates bladder muscle
• Acetylcholine cannot bind muscarinic receptors in the bladder

Correct Answer: Bethanechol has muscarinic selectivity (beta-methyl) and resistance to acetylcholinesterase, providing longer peripheral action

G S Sachin

I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.

Mail- Sachin@pharmacyfreak.com