Local Anesthetics Agents Medicinal Chemistry – PPT

Local Anesthetics: SAR of Local anesthetics Benzoic Acid derivatives; Cocaine, Hexylcaine,
Meprylcaine, Cyclomethycaine, Piperocaine.
Amino Benzoic acid derivatives: Benzocaine*, Butamben, Procaine*, Butacaine, Propoxycaine,
Tetracaine, Benoxinate.
Lidocaine/Anilide derivatives: Lignocaine, Mepivacaine, Prilocaine, Etidocaine.
Miscellaneous: Phenacaine, Diperodon, Dibucaine.*

Local Ansthetics Drugs Medicinal Chemistry

Slide 2: Introduction to Local Anesthetics

• Definition: Local anesthetics are drugs that cause reversible inhibition of nerve conduction, leading to a temporary loss of sensation in a specific area.
• Mechanism of Action: Block voltage-gated sodium channels, preventing the initiation and propagation of action potentials in neurons.
• Classification:
  • Benzoic Acid Derivatives
  • Amino Benzoic Acid Derivatives
  • Lidocaine/Anilide Derivatives
  • Miscellaneous

Slide 3: SAR of Local Anesthetics

• Core Structural Features:
  1. Lipophilic Aromatic Group: Provides affinity for lipid membranes (e.g., benzene ring).
  2. Intermediate Chain: Usually an ester (-COO-) or amide (-NHCO-) that links the aromatic group to the amine.
  3. Hydrophilic Amine: Interacts with the receptor and determines the ionized form at physiological pH.

Slide 4: Benzoic Acid Derivatives

• General Structure:
  • Lipophilic benzoic acid-based aromatic ring attached to a hydrophilic amine through an ester linkage.
• Examples:
  1. Cocaine: The prototype local anesthetic, used medically for its numbing effect but limited due to its addictive potential.
  2. Hexylcaine
  3. Meprylcaine
  4. Cyclomethycaine
  5. Piperocaine

  SAR Highlights: Modifications to the aromatic ring and alkyl chain can influence potency and duration of action.

Slide 5: Amino Benzoic Acid Derivatives

• Structure Overview: Aromatic amino benzoic acid linked to an ester group and a hydrophilic amine.
• Examples and Key Compounds:
  1. Benzocaine: Lacks amine; used topically (Synthesis required)
  2. Butamben
  3. Procaine: One of the earliest local anesthetics; short-acting (Synthesis required)
  4. Butacaine
  5. Propoxycaine
  6. Tetracaine: More potent and longer duration than procaine
  7. Benoxinate

  SAR Highlights: The ester linkage is crucial for hydrolysis by esterases, and the amino group contributes to solubility and receptor binding.

Slide 6: Synthesis of Benzocaine and Procaine

• Synthesis Overview:
  • Benzocaine:
    1. Start from p-aminobenzoic acid (PABA).
    2. Esterification reaction with ethanol in the presence of an acid catalyst.
  • Procaine:
    1. Start with PABA.
    2. React with diethylaminoethanol in the presence of a catalyst to form the ester bond.

Slide 7: Lidocaine/Anilide Derivatives

• Structure: Amide-linked derivatives, where the aromatic group is connected to an amine group through an amide bond.
• Examples:
  1. Lidocaine (Lignocaine): Widely used, rapid onset, intermediate duration
  2. Mepivacaine
  3. Prilocaine
  4. Etidocaine

  SAR Highlights: The amide bond provides greater stability compared to ester-linked anesthetics, leading to a longer duration of action. Modification on the amine group alters lipophilicity and potency.

Slide 8: Miscellaneous Local Anesthetics

• Examples:
  1. Phenacaine
  2. Diperodon
  3. Dibucaine: Highly potent and long-acting (Synthesis required)

  SAR Notes: These compounds often contain complex ring structures that enhance binding affinity and increase the duration of action.

Slide 9: Synthesis of Dibucaine

• Synthesis Overview:
  1. Start from quinoline derivatives.
  2. Formation of the amide bond with alkylamines.
  3. Modification of the structure to enhance lipophilicity and activity.

Slide 10: Comparative SAR Overview

• Ester vs. Amide Anesthetics:
  • Ester-type (e.g., Procaine): Rapidly metabolized by plasma esterases; shorter duration of action.
  • Amide-type (e.g., Lidocaine): Metabolized by hepatic enzymes; longer-lasting.
• Effect of Substituents:
  • Alkyl groups on the amine increase lipophilicity and duration.
  • Electron-donating groups on the aromatic ring enhance activity.

Slide 11: Clinical Applications

• Benzoic Acid Derivatives: Used mainly for infiltration and regional anesthesia.
• Amino Benzoic Acid Derivatives: Topical anesthetics and injections for short procedures.
• Lidocaine Derivatives: Versatile for local, epidural, and spinal anesthesia.
• Miscellaneous: Specialty uses for long-lasting effects in spinal or epidural anesthesia.

Slide 12: Conclusion

• Key Takeaways:
  • SAR insights guide the development of anesthetics with optimal properties.
  • Ester and amide linkages critically influence pharmacokinetics and metabolism.
  • Synthesis of specific local anesthetics like Benzocaine, Procaine, and Dibucaine highlight different approaches to modifying structure for activity.

Slide 13: References

• List of relevant textbooks, journals, and resources for further reading.

Local Ansthetics Drugs Medicinal Chemistry

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