SAR of Morphine Analogues

• SAR of Morphine Analogues highlights opioid receptor binding, guiding design of safer pain relievers.
• SAR of Morphine Analogues shows how structural changes modify analgesic potency and side effects.
• Morphine has a rigid, pentacyclic ring system with functional groups critical to opioid activity.

Key Features of SAR of Morphine Analogues:

1. Phenolic OH at C-3:

   • Essential for activity via H-bonding with opioid receptors.
   • Methylation (e.g., codeine) reduces potency but improves oral bioavailability.

2. Alcoholic OH at C-6:

   • Modifications affect potency/duration.
   • Oxidation to ketone (e.g., oxymorphone) boosts potency.
   • Acetylation (e.g., heroin) increases lipid solubility and brain entry.

3. C-7/C-8 Double Bond:

   • Reduction (e.g., dihydromorphine) usually increases potency.
   • Removal adds flexibility, possibly reducing selectivity.

4. Aromatic A-Ring:

   • Needed for π–π interactions with receptors.
   • Substitutions often reduce activity unless planarity/electron density are preserved.

5. Tertiary Amine at N-17:

   • Critical for activity – binds receptor’s negative site.
   • Small groups (methyl) = agonist.
   • Bulkier groups (e.g., cyclopropylmethyl) = antagonist or mixed activity.

6. N-to-Aromatic Ring Distance:

   • 2-carbon span is optimal.
   • Altering these spacing lowers activity.

7. Rigid Ring Conformation:

   • Fused ring rigidity maintains receptor-binding orientation.
   • Flexibility (in some analogues) may affect potency/selectivity.

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