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