OPIOID RECEPTORSOPIOID RECEPTORS
Chapter Chapter 2424
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)
RECEPTOR
Ionic binding region
VdW binding region
Hydrogen bondbinding region
SCAFFOLD
SCAFFOLD
RECEPTORRECEPTOR
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
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
Mu Receptor ()
* Morphine binds strongly
* Activation produces analgesia plus side effects(respiratory depression, euphoria, addiction)
* G-Protein coupled receptor
* -Receptor subtypes identified which may allow separation of analgesia from side effects
* -Receptors related to all sources of pain stimuli
Kappa Receptor ()
* Morphine binds less strongly
* Activation produces analgesia plus sedation
* Insignificant side effects
* Potential target for safe analgesics (compounds acting as agonists at , antagonists at and no activity at thereceptor).
* G-Protein-coupled receptor
* Receptors related to non-thermal pain induced stimuli
Delta Receptor ()
* Morphine binds strongly
* Receptor for enkephalins
* Activation produces analgesia plus some side effects
* G-Protein-linked receptor
* receptors related to pain induced stimuli from all sources
Sigma Receptor ()
* 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)
Blue = Agonist (Blue) = Partial agonist Red = Antagonist
Endogenous peptides-endorphin +++ +++ +++
Leu-enkephalin + +++ -Met-enkephalin ++ +++ -Dynorphin ++ + +++Opiate drugsPure agonistsMorphine, codeine +++ + +Methadone +++ - -Pethidine ++ + +Etorphine +++ +++ +++Fentanyl +++ + -Partial/mixed agonistsPentazocine + + ++Nalorphine ++ - (++)Buprenorphine (+++) - ++AntagonistsNaloxone +++ + ++Naltrexone +++ + +++
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.
Agonist hydrophobic region
H-BondHydrophobic
Ionic
Antagonist hydrophobic region
Binding Regions
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
Binding Modes for N-Phenethylmorphine
Pure agonist with enhanced activity
O
N
HO
HO..
agonistregion
antagonistregion
•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
agonistregion
antagonistregion
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
HOHO
O
N
HO
Influence of a 14-OH Group
StericClash
O
N
HO
..
O
N
HO
HO
..
OH
HO
O
N
HO..OH
StericStericClashClash
O
N
HO
..
O
N
HO
HO
..
OH
HO
O
N
HO..OH
Pure antagonist
Influence of 14-OH Group