Opioid Receptors - Guildford Advanced Courses · Opioid receptors are G protein coupled receptors...
Transcript of Opioid Receptors - Guildford Advanced Courses · Opioid receptors are G protein coupled receptors...
Graeme Henderson, School of Physiology, Pharmacology & Neuroscience
University of Bristol, UK
Opioid Receptors
1975 Discovery of the enkephalins (the first endorphins) by
Hughes & Kosterlitz at Aberdeen University
Hope – opportunity to develop new, non addictive analgesic drugs
1975 – 2016
Remifentanyl, meptazinol, tapentadol, alvemopan
(loperamide & buprenorphine)
New opioid analgesics – where are they?
Current status of receptor-selective ligands
m
Agonists (biased)
- pain
d
Agonists (biased)
- chronic pain
- depression- neuroprotection
k
Agonists
- IBS???
Antagonists
- depression?
- anticraving?
NOP
Agonists
- pain
Antagonists
- drug dependence?
- depression?
The New Hope
Biased agonists will have fewer ‘on target’ side effects
Advances in knowledge of m-opioid receptor structure
‘R’c c
Protein ‘blob’ cartoon Amino acid sequence
X-ray crystal structure3D representation
Opioid receptors are G protein coupled receptors
(m, d, k and ORL1)
all couple to Gi/Go
Opioid
receptor
N, P/Q
Calcium
channel
agonist
Reduce
neurotransmitter
release
Neurones less
excitable
• Suppresses pain transmission along pain pathways
• Lowers inhibition – activating descending inhibitory pathways
O
GRK
pp p
parrestin
OO
O
bga
bg
a
pp
arrestin
O
Downregulation
Opioid receptor regulation by GRKs/arrestins
Desensitised
Resensitisation
O
GRK
pp p
parrestin
OO
O
bga
bg
a
pp
arrestin
O
Downregulation
Opioid receptor regulation by GRKs/arrestins
Resensitisation
Novel signalling
Arrestin activated intracellular signalling cascades
Multiple signalling pathways
• Slower responses?
Biased agonists
Response A Response AResponse B Response B
Biased agonists
G proteinactivation
G proteinactivation
Arrestinsignalling
Arrestinsignalling
Opioid biased agonists
Analgesia AnalgesiaEuphoriaRespiratory depression
EuphoriaRespiratory depression
morphine
Advances in knowledge of m-opioid receptor structure
‘R’c c
Protein ‘blob’ cartoon Amino acid sequence
X-ray crystal structure3D representation
Drug docking into its binding pocket
Side on From the top
Docked over 3 million
compounds
Manglik et al., Nature 17th August 2016
In silico drug screening
Conditioned place preference
In vivo pharmacology of PZM21
Allosteric modulatorse.g. benzodiazepines at the GABAA receptor
Positive allosteric modulators (PAMs)
Alone – potentiate only those receptors activated by endorphins
+ opioid agonist – require less agonist to produce response
decreasing ‘off target’ side effects
m1/m2/M-6-G d1/d2 k1/k2/k3 NOP
• Polymorphisms
• Splice variants
• Heterodimers
OPRM1 OPRD1 OPRK1 OPRL1
Only one gene for each
Opioid receptor subtypes
m-opioid receptor polymorphisms
A118G (N40D) mutation of asparagine to aspartate at position 40
Frequency – 10 to 30%
• Post operative pain – G allele carriers may require higher opioid doses
• Alcoholics with G allele respond better to naltrexone therapy
• May alter receptor expression on the
membrane rather than drug binding
to the receptor
Heroin and morphine-6-glucuronide
receptors?????
Desensitises slowly
m-opioid receptor splice variants
m opioid receptor crystal structure
Oligomerization – dimers and more
dimer multiimer
Heteromerisation
Ligand binding to one GPCR in dimer can
enhance the affinity of binding of the other
Bivalent ligands
Synergy between
d and m agonists
Enhanced signalling?
Graeme Henderson, School of Physiology, Pharmacology & Neuroscience
University of Bristol, UK
New Opioid AnalgesicsLots of excitement and hope for the future!
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Gabapentoid Prescriptions (100,000s)Deaths mentioning pregabalin or gabapentinDeaths mentioning gabapentoids & opioids
Gabapentoid prescriptions and acute deaths
prescriptions
deaths
Time post drug (min)
Min
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vo
lum
e
(% p
red
rug
level)
drug
B
morphine
pregabalin
A
pregabalin
Min
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vo
lum
e (
ml/
min
)
Time (min)
0 1 0 2 0 3 0 4 0 5 0
0
5 0
1 0 0
1 5 0
2 0 0
0 1 0 2 0 3 0
0
2 0
6 0
8 0
1 0 0
5 mV
0.5 sec
saline
pregabalin
C
Pregabalin depresses respiration in (mice)
Time post drug (min)
Min
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vo
lum
e
(% p
red
rug
leve
l)
pregabalin
morphine or saline
0 1 0 2 0 3 0 4 0 5 0 6 0
0
2 04 0
5 0
6 0
7 0
8 0
9 0
1 0 0
Additive with morphine
The American problem
graph
The Problem in North America
Prescription opioids