opioid receptors - guildford advanced courses · opioid receptors are g protein coupled receptors...
TRANSCRIPT
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Graeme Henderson, School of Physiology, Pharmacology & Neuroscience
University of Bristol, UK
Opioid Receptors
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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?
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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
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Advances in knowledge of m-opioid receptor structure
‘R’c c
Protein ‘blob’ cartoon Amino acid sequence
X-ray crystal structure3D representation
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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
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O
GRK
pp p
parrestin
OO
O
bga
bg
a
pp
arrestin
O
Downregulation
Opioid receptor regulation by GRKs/arrestins
Desensitised
Resensitisation
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O
GRK
pp p
parrestin
OO
O
bga
bg
a
pp
arrestin
O
Downregulation
Opioid receptor regulation by GRKs/arrestins
Resensitisation
Novel signalling
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Arrestin activated intracellular signalling cascades
Multiple signalling pathways
• Slower responses?
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Biased agonists
Response A Response AResponse B Response B
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Biased agonists
G proteinactivation
G proteinactivation
Arrestinsignalling
Arrestinsignalling
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Opioid biased agonists
Analgesia AnalgesiaEuphoriaRespiratory depression
EuphoriaRespiratory depression
morphine
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Advances in knowledge of m-opioid receptor structure
‘R’c c
Protein ‘blob’ cartoon Amino acid sequence
X-ray crystal structure3D representation
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Drug docking into its binding pocket
Side on From the top
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Docked over 3 million
compounds
Manglik et al., Nature 17th August 2016
In silico drug screening
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Conditioned place preference
In vivo pharmacology of PZM21
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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
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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
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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
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Heroin and morphine-6-glucuronide
receptors?????
Desensitises slowly
m-opioid receptor splice variants
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m opioid receptor crystal structure
Oligomerization – dimers and more
dimer multiimer
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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?
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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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Dru
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Pre
gab
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abap
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in 1
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Year
Gabapentoid Prescriptions (100,000s)Deaths mentioning pregabalin or gabapentinDeaths mentioning gabapentoids & opioids
Gabapentoid prescriptions and acute deaths
prescriptions
deaths
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Time post drug (min)
Min
ute
vo
lum
e
(% p
red
rug
level)
drug
B
morphine
pregabalin
A
pregabalin
Min
ute
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
ute
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
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The American problem
graph
The Problem in North America
Prescription opioids