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OPIOID RECEPTORS

Chapter 24. OPIOID RECEPTORS. Receptor Theories. Beckett-Casy hypothesis * Single opioid receptor interacts with morphine * Ionic binding region (CO 2 - ) interacts with positive N + * Hydrophobic binding region interacts with aromatic ring * Hydrogen bonding region interacts with phenol

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OPIOID RECEPTORS

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  1. Chapter 24 OPIOID RECEPTORS

  2. Receptor Theories Beckett-Casy hypothesis * Single opioid receptor interacts with morphine * Ionic binding region (CO2-) interacts with positive N+ * Hydrophobic binding region interacts with aromatic ring * Hydrogen bonding region interacts with phenol * Hollow region accepts carbon bridge (C-15 and C-16)

  3. Ionic binding region VdW binding region Hydrogen bond binding region RECEPTOR

  4. SCAFFOLD

  5. SCAFFOLD RECEPTOR

  6. Receptor Theories Drawbacks with the Beckett-Casy hypothesis * Ethylene bridge is not important in some analgesics (fentanyl) * No account for extra binding regions found by extension * Does not explain different SAR results (e.g. meperidine vs morphine) * Does not explain mixed antagonist/agonist properties

  7. Receptor Theories Multiple Analgesic Receptors * Three different analgesic receptors (mu, kappa and delta) * Binding sites for all three receptors contain ionic, hydrogen bonding and hydrophobic regions as proposed by Beckett-Casy * Activation of all three produce analgesia, but differ in other effects * All three interact with morphine * Potential to target drugs selectively

  8. Mu Receptor (m) * Morphine binds strongly * Activation produces analgesia plus side effects (respiratory depression, euphoria, addiction) * G-Protein coupled receptor * m-Receptor subtypes identified which may allow separation of analgesia from side effects * m-Receptors related to all sources of pain stimuli

  9. Kappa Receptor (k) * Morphine binds less strongly * Activation produces analgesia plus sedation * Insignificant side effects * Potential target for safe analgesics (compounds acting as agonists at k, antagonists at m and no activity at the d receptor). * G-Protein-coupled receptor * k Receptors related to non-thermal pain induced stimuli

  10. Delta Receptor (d) * Morphine binds strongly * Receptor for enkephalins * Activation produces analgesia plus some side effects * G-Protein-linked receptor * d receptors related to pain induced stimuli from all sources

  11. Sigma Receptor (s) * Activated by some opoid analgesics (e.g. nalorphine) * Non-analgesic, non-opoid receptor * Activation produces hallucinogenic effects * Thought to be responsible for effects of phencyclidine (PCP) (Angel Dust)

  12. Main effects of opioids at opioid receptors Blue = Agonist (Blue) = Partial agonist Red = Antagonist

  13. Agonists vs Antagonists * Why should small changes in structure (e.g. N-methyl to N-allyl) change an agonist to an antagonist at a specific receptor? * Proposed that specific receptors have additional hydrophobic binding regions which lead to agonist or antagonist activity.

  14. H-Bond Hydrophobic Antagonist hydrophobic region Ionic Agonist hydrophobic region Binding Regions

  15. HO HO HO O O O .. .. N N N Me .. Me HO HO HO Binding Modes for Morphine Morphine incapable of reaching either of the extra hydrophobic regions

  16. HO O N .. HO Binding Modes for N-Phenethylmorphine Pure agonist with enhanced activity

  17. HO HO O O .. N N .. HO HO Binding Modes for N-Phenethylmorphine antagonist region agonist region • Aromatic ring pushed beyond antagonist region • Correct distance to bind to agonist region

  18. HO HO HO O O O .. .. N N N .. HO HO HO Binding Modes for N-Allylmorphine antagonist region agonist region • Allyl group binds well to the antagonist region • Allyl group forms a weak interaction with the agonist region • Antagonist with weak agonist properties

  19. HO HO O O O .. .. N N N OH OH .. HO HO Steric Clash HO Influence of a 14-OH Group

  20. HO HO O O O .. .. N N N OH OH .. HO HO Steric Clash HO Influence of 14-OH Group Pure antagonist

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