opIoid receptor theories

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OPIOID RECEPTORS Chapter 24

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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 * Hollow region accepts carbon bridge (C-15 and C-16)

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RECEPTOR Ionic binding region VdW binding region Hydrogen bond binding region

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SCAFFOLD

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SCAFFOLD RECEPTOR

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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

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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 Receptor Theories

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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

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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

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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

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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)

Main effects of opioids at opioid receptors:

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

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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 .

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

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

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

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

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

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

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

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