SAR of morphine analogues MCQs With Answer

SAR of morphine analogues MCQs With Answer is an essential review for B. Pharm students studying opioid chemistry and pharmacology. This concise, keyword-rich introduction covers structure-activity relationships (SAR) of morphinans, roles of the 3‑OH phenol, 4,5‑epoxy bridge, N‑substitution, 6‑position modifications, 14‑hydroxylation, lipophilicity and metabolism (e.g., glucuronidation to M6G). Understanding how these structural changes affect mu‑opioid receptor affinity, potency, agonist/antagonist behavior and BBB penetration is vital for drug design and clinical pharmacology. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. Which functional group at position 3 of morphine is most critical for high mu opioid receptor activity?

• A free phenolic hydroxyl (3‑OH)
• A methoxy group (3‑OCH3)
• An acetyl group (3‑OCOCH3)
• No substituent at position 3

Correct Answer: A free phenolic hydroxyl (3‑OH)

Q2. Methylation of the 3‑OH in morphine (as in codeine) mainly causes which effect?

• Complete loss of opioid activity
• Conversion into an opioid antagonist
• Decreased receptor affinity with prodrug behavior requiring O‑demethylation
• Increased polarity and reduced BBB penetration

Correct Answer: Decreased receptor affinity with prodrug behavior requiring O‑demethylation

Q3. Diacetylation of morphine at positions 3 and 6 (heroin) increases CNS potency primarily because:

• It directly increases intrinsic receptor efficacy
• It increases lipophilicity and accelerates BBB penetration
• It prevents metabolism by glucuronidation
• It blocks the 4,5‑epoxy bridge making the molecule more flexible

Correct Answer: It increases lipophilicity and accelerates BBB penetration

Q4. Introduction of an N‑allyl or N‑cyclopropylmethyl substituent on morphine derivatives typically results in:

• Greater mu receptor agonism
• Selective delta receptor agonism
• Opioid receptor antagonism or mixed agonist‑antagonist behavior
• Increased metabolic clearance by CYP enzymes

Correct Answer: Opioid receptor antagonism or mixed agonist‑antagonist behavior

Q5. Addition of a hydroxyl group at the 14‑position (14‑OH) in morphinan derivatives generally leads to:

• Decreased mu affinity and reduced potency
• Increased mu affinity and greater analgesic potency
• Conversion to a peripheral‑only opioid
• Loss of activity due to steric hindrance

Correct Answer: Increased mu affinity and greater analgesic potency

Q6. Saturation of the 7,8 double bond (7,8‑dihydro modification) in morphine to give hydromorphone analogues commonly results in:

• Marked loss of analgesic activity
• Increased potency and faster onset
• Conversion to an antagonist scaffold
• Elimination of the 3‑OH functionality

Correct Answer: Increased potency and faster onset

Q7. Which metabolic product of morphine is mainly responsible for additional analgesic activity after morphine administration?

• Morphine‑3‑glucuronide (M3G)
• Morphine‑6‑glucuronide (M6G)

Correct Answer: Morphine‑6‑glucuronide (M6G)

Q8. The 4,5‑epoxy bridge in morphine contributes to activity by:

• Preventing hydrogen bonding to the receptor
• Maintaining the 3D conformation required for receptor binding
• Increasing metabolic stability exclusively
• Making the molecule entirely lipophilic

Correct Answer: Maintaining the 3D conformation required for receptor binding

Q9. Which statement best describes why heroin (diacetylmorphine) is more rapidly CNS‑active than morphine?

• Heroin is a stronger intrinsic agonist at the mu receptor than morphine
• Heroin resists hepatic metabolism so higher plasma levels persist
• Heroin’s acetate esters increase lipophilicity and BBB transport; it is then deacetylated to active metabolites in brain
• Heroin contains an N‑allyl substituent that increases receptor binding

Correct Answer: Heroin’s acetate esters increase lipophilicity and BBB transport; it is then deacetylated to active metabolites in brain

Q10. Which chemical change typically converts an opioid agonist into a competitive antagonist?

• Addition of a 3‑methoxy group
• N‑methylation of the tertiary amine
• Substitution of the N‑methyl with N‑allyl or N‑cyclopropylmethyl
• Introduction of a 14‑hydroxyl group

Correct Answer: Substitution of the N‑methyl with N‑allyl or N‑cyclopropylmethyl

Q11. Codeine acts as an analgesic primarily because it:

• Has higher mu receptor affinity than morphine
• Is an active agonist without metabolism
• Is a prodrug converted to morphine by O‑demethylation in the liver
• Is blocked from glucuronidation

Correct Answer: Is a prodrug converted to morphine by O‑demethylation in the liver

Q12. Which modification is associated with increased oral bioavailability of a morphine analogue?

• Adding multiple polar hydroxyl groups
• Esterification of hydroxyl groups to form more lipophilic esters
• Converting the tertiary amine to a quaternary ammonium
• Removing the 3‑OH phenolic group entirely

Correct Answer: Esterification of hydroxyl groups to form more lipophilic esters

Q13. The typical pharmacophore distance between the protonated tertiary nitrogen and the 3‑OH phenolic group in opioid agonists is approximately:

• 2.0 Å
• 3.5 Å
• 5.5 Å
• 10.0 Å

Correct Answer: 5.5 Å

Q14. Which of the following enzymes predominantly glucuronidates morphine to M3G and M6G?

• CYP3A4
• UGT2B7
• MAO‑A
• CYP2D6

Correct Answer: UGT2B7

Q15. The introduction of a 6‑keto function (as in oxymorphone) compared to morphine typically results in:

• No change in potency
• Increased potency and altered pharmacokinetics
• Complete loss of activity
• Conversion to an opioid antagonist

Correct Answer: Increased potency and altered pharmacokinetics

Q16. Which structural class does etorphine belong to and what is notable about its potency?

• Morphinan class; low potency relative to morphine
• Oripavine class; extremely high potency (used in veterinary medicine)
• Benzomorphan class; selective delta receptor agonist
• Synthetic fentanyl class; weak mu agonist

Correct Answer: Oripavine class; extremely high potency (used in veterinary medicine)

Q17. Which modification tends to reduce brain penetration of morphine analogues?

• Conversion to lipophilic esters
• Formation of polar glucuronide conjugates
• Adding a 14‑hydroxyl group
• Replacing N‑methyl with N‑propyl

Correct Answer: Formation of polar glucuronide conjugates

Q18. Which statement about morphine‑3‑glucuronide (M3G) is correct?

• M3G is a potent mu agonist responsible for analgesia
• M3G is inactive at opioid receptors and may contribute to neuroexcitatory effects
• M3G is formed by CYP3A4 oxidation
• M3G readily crosses the BBB and is the main analgesic metabolite

Correct Answer: M3G is inactive at opioid receptors and may contribute to neuroexcitatory effects

Q19. Which structural element is primarily responsible for ionic interaction with the opioid receptor (Asp residue)?

• The phenolic 3‑OH group
• The protonated tertiary nitrogen
• The 4,5‑epoxy bridge oxygen
• The 14‑OH substituent

Correct Answer: The protonated tertiary nitrogen

Q20. Buprenorphine’s partial agonist profile is largely due to:

• A small, unsubstituted N‑methyl group
• A highly lipophilic, bulky scaffold with high receptor affinity and slow dissociation
• Lack of a 3‑OH phenol
• Rapid metabolism to full agonists

Correct Answer: A highly lipophilic, bulky scaffold with high receptor affinity and slow dissociation

Q21. Which modification generally increases mu receptor selectivity over other opioid receptors?

• Introduction of bulky N‑alkyl chains exclusively
• 14‑hydroxylation in morphinan derivatives
• Removing the 3‑OH phenolic group
• Converting the tertiary amine to quaternary ammonium

Correct Answer: 14‑hydroxylation in morphinan derivatives

Q22. Which of the following is NOT a semisynthetic morphine derivative?

• Hydromorphone
• Oxymorphone
• Fentanyl
• Heroin (diacetylmorphine)

Correct Answer: Fentanyl

Q23. Opening or removal of the 4,5‑epoxy bridge in morphine analogues typically results in:

• Retention of full opioid agonist potency
• Loss or marked reduction of opioid activity due to conformational change
• Creation of selective kappa agonists
• Increased oral bioavailability

Correct Answer: Loss or marked reduction of opioid activity due to conformational change

Q24. Which modification commonly increases metabolic conversion to the active M6G metabolite instead of inactive conjugates?

• Methylation of the 3‑OH
• Retention of free 3‑OH allowing UGT2B7 glucuronidation at position 6 as well
• Removal of the 6‑OH or 6‑keto
• Conversion of tertiary amine to a quaternary amine

Correct Answer: Retention of free 3‑OH allowing UGT2B7 glucuronidation at position 6 as well

Q25. Naloxone’s rapid reversal of opioid overdose is primarily due to which structural property?

• High oral bioavailability
• Small, lipophilic structure with N‑allyl substituent that confers antagonist activity and rapid CNS penetration
• Formation of active metabolites with long duration
• Lack of a protonatable nitrogen

Correct Answer: Small, lipophilic structure with N‑allyl substituent that confers antagonist activity and rapid CNS penetration

Q26. Which change to the 3‑OH of morphine would most likely eliminate direct receptor hydrogen bonding but allow prodrug behavior?

• Replace with an ether (3‑O‑CH3)
• Replace with an OH group at position 6 instead
• Introduce a 14‑OH group
• Remove the aromatic ring A entirely

Correct Answer: Replace with an ether (3‑O‑CH3)

Q27. Which derivative demonstrates that small modifications at C‑6 can markedly change activity: hydromorphone differs from morphine primarily by which change?

• Loss of the 3‑OH
• Reduction of the 7,8 double bond and oxidation at C‑6 (6‑ketone)
• Addition of a 14‑OH
• Conversion of the tertiary amine to quaternary form

Correct Answer: Reduction of the 7,8 double bond and oxidation at C‑6 (6‑ketone)

Q28. Which structural class includes pentazocine, a mixed agonist‑antagonist, and differs from classic morphinans?

• Benzomorphan class
• Oripavine class
• Fentanyl family
• Morphinan class

Correct Answer: Benzomorphan class

Q29. Which modification is most likely to convert an opioid agonist into a compound with reduced central effects but preserved peripheral effects?

• Increasing lipophilicity
• Converting to a quaternary ammonium salt to reduce BBB penetration
• Introducing an N‑allyl group
• Adding a 14‑hydroxyl group

Correct Answer: Converting to a quaternary ammonium salt to reduce BBB penetration

Q30. Which metabolic pathway predominantly forms morphine‑3‑glucuronide (M3G) and morphine‑6‑glucuronide (M6G)?

• CYP2D6 oxidative demethylation
• Sulfation by SULT enzymes
• Glucuronidation by UDP‑glucuronosyltransferases
• Monoamine oxidase metabolism

Correct Answer: Glucuronidation by UDP‑glucuronosyltransferases

Q31. Which structural feature contributes to the high potency of etorphine compared with morphine?

• Smaller molecular size
• Oripavine scaffold with extended substitutions enhancing receptor interactions
• Lack of a tertiary nitrogen
• Complete removal of the 3‑OH group

Correct Answer: Oripavine scaffold with extended substitutions enhancing receptor interactions

Q32. Which modification is commonly used to design long‑acting opioid antagonists for oral dosing (e.g., naltrexone)?

• Shortening the carbon chain at C‑6
• Introducing substituents that increase oral bioavailability and slow clearance (e.g., cyclopropylmethyl N‑substitution with metabolic stability)
• Elimination of all hydroxyl groups
• Converting tertiary amine to primary amine

Correct Answer: Introducing substituents that increase oral bioavailability and slow clearance (e.g., cyclopropylmethyl N‑substitution with metabolic stability)

Q33. The primary role of the aromatic (phenyl) ring A in morphine analogues is to:

• Provide a site for glucuronidation
• Participate in hydrophobic and π‑stacking interactions with the receptor
• Act as the protonatable center for ionic bonding
• Prevent passage across the BBB

Correct Answer: Participate in hydrophobic and π‑stacking interactions with the receptor

Q34. Which of the following modifications is most likely to reduce mu‑receptor binding affinity dramatically?

• Replacing the protonatable tertiary nitrogen with a non‑protonatable tertiary amine
• Maintaining the 3‑OH phenol
• Adding a small methyl at N‑position
• Introducing a 14‑OH

Correct Answer: Replacing the protonatable tertiary nitrogen with a non‑protonatable tertiary amine

Q35. Which opioid analgesic is a semisynthetic derivative with greater potency than morphine due to 14‑hydroxylation and 6‑keto modifications?

• Codeine
• Oxymorphone
• Fentanyl
• Morphine‑3‑glucuronide

Correct Answer: Oxymorphone

Q36. Which structural change explains why codeine is less potent than morphine but still analgesic?

• It has an additional 14‑OH
• The 3‑OH is methylated (3‑OCH3), reducing direct receptor affinity but allowing metabolism to morphine
• Its tertiary amine is quaternized
• It lacks the 4,5‑epoxy bridge

Correct Answer: The 3‑OH is methylated (3‑OCH3), reducing direct receptor affinity but allowing metabolism to morphine

Q37. Which statement best describes the influence of lipophilicity on morphine analogue activity?

• Higher lipophilicity always reduces CNS potency
• Increased lipophilicity generally enhances BBB penetration and often increases onset and potency
• Lipophilicity has no effect on pharmacokinetics
• Only polar molecules can cross the BBB effectively

Correct Answer: Increased lipophilicity generally enhances BBB penetration and often increases onset and potency

Q38. Which change at the N‑position would you expect in a clinically used opioid antagonist like naloxone?

• N‑methyl preserved as in morphine
• N‑allyl substitution producing antagonist activity
• N‑propyl leading to increased agonism
• Removal of N substituent entirely

Correct Answer: N‑allyl substitution producing antagonist activity

Q39. Which metabolite is primarily associated with analgesic activity after morphine administration in humans?

• Morphine‑3‑glucuronide (M3G)
• Morphine‑6‑glucuronide (M6G)
• Hydromorphone formed in large amounts clinically
• Morphine sulfate

Correct Answer: Morphine‑6‑glucuronide (M6G)

Q40. Which structural modification explains the rapid onset action of diamorphine (heroin) compared with morphine?

• Addition of polar sulfate groups
• Acetylation at 3 and 6 positions increasing lipophilicity and BBB crossing
• Conversion to a quaternary ammonium salt
• Introduction of a bulky 14‑substituent preventing CNS entry

Correct Answer: Acetylation at 3 and 6 positions increasing lipophilicity and BBB crossing

Q41. Which modification would most likely increase the likelihood of conjugation by UGT enzymes?

• Removal of all hydroxyl groups
• Presence of free phenolic hydroxyls such as 3‑OH and/or 6‑OH
• Converting hydroxyls into esters that are permanently resistant to hydrolysis
• Replacing the protonatable nitrogen with carbon

Correct Answer: Presence of free phenolic hydroxyls such as 3‑OH and/or 6‑OH

Q42. Which clinical opioid is a partial agonist with high affinity and slow dissociation from mu receptors, often used in opioid dependence treatment?

• Morphine
• Buprenorphine
• Hydromorphone
• Naloxone

Correct Answer: Buprenorphine

Q43. Which structural change is characteristic of fentanyl compared to morphine derivatives?

• It retains the morphinan skeleton
• It is an anilidopiperidine lacking the morphinan scaffold and is highly lipophilic
• It contains a 4,5‑epoxy bridge identical to morphine
• It has a 3‑phenolic OH essential for activity

Correct Answer: It is an anilidopiperidine lacking the morphinan scaffold and is highly lipophilic

Q44. Which empirical SAR observation explains why replacement of the N‑methyl with bulkier groups shifts efficacy?

• Bulky N‑substituents always increase agonist efficacy
• Large N‑substituents sterically block the receptor activation conformation, often producing antagonists or partial agonists
• N‑substituents have no effect on receptor interactions
• Only the 3‑OH determines agonist vs antagonist action

Correct Answer: Large N‑substituents sterically block the receptor activation conformation, often producing antagonists or partial agonists

Q45. Which analog demonstrates that acetylation at C‑6 can increase potency: hydrocodone, hydromorphone, or heroin?

• Hydrocodone (no acetylation at both 3 and 6)
• Hydromorphone (7,8‑dihydro and 6‑keto, not acetylated)
• Heroin (diacetylmorphine; acetylation at 3 and 6 increases BBB entry and potency)
• All are identical in structural changes

Correct Answer: Heroin (diacetylmorphine; acetylation at 3 and 6 increases BBB entry and potency)

Q46. Which property primarily determines whether a morphine analogue will be centrally active?

• Ability to form glucuronide conjugates
• Degree of lipophilicity and ability to cross the blood‑brain barrier
• Presence of a 14‑OH only
• Number of carbon atoms in the molecule

Correct Answer: Degree of lipophilicity and ability to cross the blood‑brain barrier

Q47. Which opioid class contains agents that are structurally unrelated to morphine but can be far more potent due to lipophilicity and receptor interactions?

• Morphinans
• Anilidopiperidines (e.g., fentanyl)
• Oripavines only

Correct Answer: Anilidopiperidines (e.g., fentanyl)

Q48. Which structural modification is most often associated with increasing potency while maintaining agonist activity in morphinan series?

• Methylation of 3‑OH to 3‑OCH3 without metabolic activation
• 14‑hydroxylation combined with 6‑keto or 7,8‑dihydro changes
• Removal of the tertiary amine
• Conversion into quaternary ammonium derivatives

Correct Answer: 14‑hydroxylation combined with 6‑keto or 7,8‑dihydro changes

Q49. Which statement correctly contrasts morphine and its glucuronide metabolites in terms of CNS penetration?

• M6G and M3G penetrate the BBB more readily than morphine
• Glucuronide conjugates are more polar and generally have reduced BBB penetration compared to morphine, although M6G may still exert central effects
• Glucuronides are lipophilic and rapidly cross the BBB
• Metabolites are identical in BBB penetration to morphine

Correct Answer: Glucuronide conjugates are more polar and generally have reduced BBB penetration compared to morphine, although M6G may still exert central effects

Q50. Which summary statement best captures key SAR principles for morphine‑like opioids relevant to drug design?

• Only the tertiary nitrogen matters; hydroxyls are irrelevant
• Critical features include a protonatable tertiary nitrogen, a 3‑OH phenol for hydrogen bonding, correct spatial distance between these groups (~5.5 Å), and modifications at N, C‑6 and C‑14 to alter potency, selectivity, and pharmacokinetics
• Lipophilicity always reduces potency and should be minimized
• Any change to the scaffold yields a full antagonist

Correct Answer: Critical features include a protonatable tertiary nitrogen, a 3‑OH phenol for hydrogen bonding, correct spatial distance between these groups (~5.5 Å), and modifications at N, C‑6 and C‑14 to alter potency, selectivity, and pharmacokinetics

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