• To  analgesic activity &  side effects (addiction liability & respiratory depression)

• Strategies used:
1) Variation of substitution
2) Drug extension
3) Simplification
4) Rigidification

[1] Variation of substituents

Substituents on positions 3, 6 & 17 (N-atom)

R Methyl Ethyl Propyl Butyl Pentyl Hexyl

Analgesic Agonist  & Zero Agonist 14 X activity Mixed opioid

Activity Antagonist  (Slightly agonist) of morphine agonist–
antagonist

Comment  Size of alkyl group (R) on N-atom Larger group as Extra binding Nalorphine
from methyl (Me) to butyl (Bu)  pentyl or hexyl  group
activity drops to zero activity recovers
slightly


 [2] Drug extension [Addition of extra-binding group]

14-hydroxy morphine (Oxymorphine) N-Phenethyl morphine

2.5 X activity of morphine 14 X activity of morphine

Introduction of 14 OH group  make extra-hydrogen bonding interaction Phenethyl group Aromatic ring binds to
with amino acid residue on opioid receptor (extra-binding region)  activity extra-hydrophobic binding region at the receptor  activity

 size of N-substituent to 3-5 carbons (Especially where unsaturation “e.g. allyl” or small carbocyclic rings “e.g. cyclopropyl” are included)

 compounds that are antagonists at some or all opioid receptor types

Mixed agonist/antagonist analgesics Pure antagonists (No analgesic activity)

Nalorphine Nalbuphine Naloxone Naltrexone
(N-Allylnormorphine)


 Nalorphine Nalbuphine Naloxone Naltrexone
 Strong antagonistic  Synthetic MOA: 8 times more active
effects at MOR mixed agonist-antagonist Bind to the analgesic receptors without switching them on than naloxone
thus blocking morphine binding  as an antagonist
 Antagonist or partial
 High-efficacy agonistic 1) No analgesic activity
agonist at MOR 2) No side effects of morphine (advantage)
effects at KOR
 Agonist at KOR Administration to opioid-dependent individuals (Diagnosis):
cause symptoms of opioid withdrawal e.g. agitation, nausea,
vomiting, a fast heart rate & sweating.
• Weak analgesic activity. Uses: • Considered as opioid inverse agonist Uses:
• 1) Relief of moderate to
Without (free from) • Not used in treating opiate addiction Management of
severe pain.
the undesired side
2) As a supplement to • Uses: alcohol & opioid
effects. balanced anesthesia, Useful in treating acute (emergency cases) of opioid addiction.
• Withdrawn due to for preoperative &
overdose (Antidote), why?
undesirable psychotic postoperative analgesia.
effects 3) For obstetrical analgesia It reverses their CNS & respiratory depression & hypotension
during labor & delivery.

How can a compound (e.g. Nalorphine) be an antagonist of morphine Naloxone is a pure opioid antagonist

but acts at the same time as agonist & produce analgesia? (14-OH group hinder binding of N-allyl group to agonistic binding region)


 [3] Simplification (Drug dissection)
(simplification = dissection = disjunction = trimming = dissociation)
1) Removing ring E
2) Removing ring D (Ether bridge)
3) Removing rings C & D
4) Removing rings B, C & D
5) Removing rings B, C, D & E

(1) Removing of ring E

✓ Complete loss of activity.

✓ Basic nitrogen  essential for
analgesic activity.

(2) Removing of ring D (Ether bridge)  (Morphinans)

 Morphinans are more potent & longer acting (longer duration) than morphine, why?

• Ether bridge, 6-OH & 7,8–double bond  not essential for activity
• Removing of them allows:
1) Greater lipophilicity  BBB penetration.
2) Greater flexibility → binding affinity at all opioid receptor compared with morphine.
3) Not metabolized in the liver like morphine.
 Disadvantages: higher toxicity & comparable dependence characteristics

 The modifications carried on morphine when carried on morphinans

 the same biological results.


 Opioid agonists Mixed agonists /antagonists

(-)-Levorphanol Dextromethorphan N-Phenethyl- Levallorphan Butorphanol

levorphanol

5X more potent Etherification of 3-OH 15X more potent Antagonist 5X as Nalbuphine

than morphine of Dextrorphan than morphine more potent than
Nalorphine
• Lacks analgesic, N-Phenethyl  Replacement of ✓ Partial agonist & antagonist
Levo (-)- Dextro (+) respiratory lipophilicity & N-methyl by N-allyl  activity at MOR
isomer isomer depressant & abuse extra-binding group morphine antagonist ✓ Partial agonist at KOR.
Levorphanol Dextrorphan potential Uses:
 activity
• Retains antitussive Intranasal Parenterally
Opioid antitussive
action
activity activity spray
management management
of migraine of moderate-
to-severe pain