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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2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Dru

g R

elat

ed D

eath

s

Pre

gab

alin

an

d G

abap

enti

n P

resc

rip

tio

ns

in 1

00,0

00

Year

Gabapentoid Prescriptions (100,000s)Deaths mentioning pregabalin or gabapentinDeaths mentioning gabapentoids & opioids

Gabapentoid prescriptions and acute deaths

prescriptions

deaths

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

The American problem

graph

The Problem in North America

Prescription opioids