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)
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds

3. mor-037 AIF RECEPTOR Ionic binding region VdW binding region
Hydrogen bond
binding region
mor-037 AIF
RECEPTOR

4. SCAFFOLD
MOR036.WAV

5. SCAFFOLD
mor-038 AIF
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
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds

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
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds

8. * Morphine binds strongly
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
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds

9. * Morphine binds less strongly
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
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds

10. * Morphine binds strongly * Receptor for enkephalins
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
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds

11. * Activated by some opoid analgesics (e.g. nalorphine)
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)
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds

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.
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds

14. Binding Regions H-Bond Hydrophobic Antagonist hydrophobic region Ionic
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds

15. Binding Modes for Morphine.. N HO O Me O N HO .. Me
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds
Morphine incapable of reaching either of the extra hydrophobic regions

16. Binding Modes for N-PhenethylmorphineHO ..
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds
Pure agonist with enhanced activity

17. Binding Modes for N-PhenethylmorphineHO N .. O N HO ..
antagonist
region
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds
agonist
region
Aromatic ring pushed beyond antagonist region
Correct distance to bind to agonist region

18. Binding Modes for N-Allylmorphine.. N HO O .. HO O N
antagonist
region
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds
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. Influence of a 14-OH GroupHO .. OH HO O N .. OH
Steric
Clash
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds

20. Influence of 14-OH Group Steric Clash Pure antagonist HO O O N .. N OH
The presence of the phenol is an added complication thought and so it was decided to concentrate oin finding a synthesis on the following simpler compounds
Pure antagonist