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    Add as FriendStructure Pruning Technique

    by: Pramod

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    1 : STRUCTURE PRUNING TECHNIQUE
    2 : STRUCTURE PRUNING Structure pruning is the refinement of the lead compound to improve the activity and reduce the unwanted effects. In other words, structure pruning means cutting of the structure and seeing its activity. This is one of the technique for the optimization of lead compound. Structure pruning is applied for many of the compounds which results in simplification of the drug so that it will be easy to synthesize the derivatives. It is a technique much applied to the morphine obtained from opium. Generally morphine is having analgesic activity and possess complex structure, but this technique makes simplification of the morphine for easy synthesis of its derivatives. Hence the structure pruning technique of morphine is given below.
    3 : ABOUT MORPHINE Morphine Morphine: Active principle of opium, one of the best painkillers More effective for chronic pain Possess large number of side-effects Hence, gained interest for structure pruning Chemistry: Molecular Formula: C17H19NO3 Contains Phenanthrene basic ring, an ether linkage, one phenolic one alcoholic -OH group, one double bond and one N-methyl group. Ring-A : Benzene ring with one phenolic –OH . Ring-B : Cyclohexane ring Ring-C : Cyclohexene ring (one double bond) and one alcoholic -OH Ring-D : Tetrahydrofuran / ring formed due to ether bridge Ring-E : N-methyl piperidine
    4 : Morphine Outcome: Complete loss of activity. Conclusion: Basic nitrogen is essential for analgesic activity. MORPHINE-STRUCTURE PRUNING Removing ring-E Removing Ring-E:
    5 : MORPHINE-STRUCTURE PRUNING Morphine N-methyl morphinan (Morphinan Derivative) Removal of ring-D, two -OH groups a double bond in ring-C Removing Ring-D: Outcome: N-Methyl morphinan possess only 20% activity of Morphine. Conclusion: Phenolic –OH group to be retained for further studies. Morphinans Gives
    6 : Morphine Levorphanol Removing Ring-D: Removal of ring-D, 6-OH group a double bond in ring-C MORPHINE-STRUCTURE PRUNING Outcome: Levorphanol is 5x more active than Morphine. Longer duration of action, with increased side effects. Levellorphan 5x more potent antagonist activity than nalorphan. Conclusion: Ring-D is not essential for the activity. Retaining of phenolic –OH group increases the activity at C-3 position for Morphinans. Chain extension at nitrogen greatly influences the type of activity potency of Morphinans. Levallorphan Morphinans Gives
    7 : Metazocene Morphine Removing Ring- C D: MORPHINE-STRUCTURE PRUNING Removal of ring- C D Outcome: Metazocene possess same activity as that of Morphine Phenazocene, 4x more potent than Morphine without dependence. Many of Benzomorphans possess Hallucinogenic effects. Conclusion: Ring C and D are not essential for the activity. Benzomorphans retain analgesic activity Chain extension at Nitrogen atom influences the analgesic activity without dependence. Phenazocene Benzomorphans Gives
    8 : Morphine Ketobemidone Removing Ring- B,C, D: MORPHINE-STRUCTURE PRUNING Removal of ring-B, C, D 4-Phenylpiperidines Gives Outcome: Ketobemidone, 6x more potent than Morphine. Fentanyl, 100x more potent than Morphine. Piperidines retain addiction respiratory centre depression. Conclusion: Ring B, C, D are not essential for analgesic activity. Aromatic ring and basic nitrogen are essential for activity, but the phenolic group is not. Fentanyl
    9 : Morphine Methadone MORPHINE-STRUCTURE PRUNING Removing Ring- B,C, D, E: Removal of ring-D, 6-OH group a double bond in ring-C Methadone Gives Outcome: Methadone has a single chiral centre. R enantiomer is 2x more powerful than Morphine with less severity of side effects. S enantiomer is inactive. Conclusion: Rings B, C, D, E are not essential for activity. Stereoisomerism in Methadone place a major role for activity of the compound.
    10 : Any Queries..?
    11 : Thank you

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