Preclinical development of novel kappa opioid compounds for the - - PowerPoint PPT Presentation

Dr Bronwyn Kivell

Centre for Biodiscovery Victoria University of Wellington

Preclinical development of novel kappa opioid compounds for the treatment of drug-addiction

Addiction and Reward

ABUSE Withdrawal Craving

> No approved pharmacotherapies for treatment of psychostimulant addiction

Kappa opioid systems & Addiction

Co-Localization of KOPr and DAT

Svingos et al., 2001

5.0 10.0 15.0 100 200 300

Heterozygote Knock-Out Cocaine Dose (mg/kg)

DA

Wild-type Saline * * *

Kappa opioids regulate Dopamine levels

Chefer et al., J Neuroscience (2005)

• KOPr Agonists Exert

‘Cocaine-Antagonist’ Like Effects in Animal Models of Drug-Seeking

• Attenuates i.v. cocaine self-

administration

• Attenuation of cocaine—

prime induced cocaine-seeking in animal models of relapse

• Attenuation of cocaine

induced hyperactivity Schenk S, Partridge B, Shippenberg TS (1998-2001)

Cocaine/ KOPr Agonist Interactions

ANTI-COCAINE EFFECTS

Cocaine self- admin Extinction (saline) Reinstatement > Drug-prime > KOPr treatment

• Drug-primed reinstatement model

Reinstatement Test

Modified analogues C-2 Salvinorin A EC50: 0.030 nM C-16

Salvia divinorum

Modified C16 analogues Modified C2 analogue

Baseline Extinction Control 0.1 0.3 100 200 300 400

* *

Treatment Responses

Treatment

Responses

Control 0.3 1 100 200 300 400

** Treatment

Responses

Control 0.1 0.3 1.0 50 100 150

** **

ANTI-ADDICTION EFFECTS

Cocaine prime-induced reinstatement

#1 C16 analogue C2 Analogue #2 C16 analogue

LONGER DURATION OF ACTION

10 20 30 40 50 60 70 80 90 100 110 120 130 140 150

• 10

10 20 30 40

Veh SalA (1 mg/Kg) C2 analogue (1 mg/Kg)

* **** ***

# # #

^^^^ Time (min) %MPE

Tail flick latency

10 20 30 40 50 60 70 80 90 100 110 120 130 140 150

• 10

10 20 30 40

Vehicle #1 C16 analogue (1 mg/kg) SalA (1 mg/Kg)

Time (min) %MPE *** *** *** ** * * *

Tail withdrawal assay

Spontaneous locomotion

Sedation

V e h i c l e N

• v

e l a n a l

• g

u e 500 1000 1500 2000

Total ambulatory counts

Vehicle Novel analogue 500 1000 1500 2000

Total ambulatory counts

V e h i c l e N

• v

e l a n a l

• g

u e 500 1000 1500 2000

Total Ambulatory Counts

SIDE EFFECTS

Sedation: Locomotor activity

#1 C16 analogue C2 Analogue #2 C16 analogue

SIDE EFFECTS

Aversion: Conditioned place aversion

Time spent in chamber A (%)

V e h i c l e N

• v

e l a n a l

• g

u e 20 40 60 80

Pre post Time in paired chamber (%)

20 40 60 80

vehicle Novel analogue

*

Pre-test Post-test

#1 C16 analogue C2 Analogue

Time (s)

Vehicle novel analogue Vehicle novel analogue Vehicle novel analogue

50 100 150 200 250

** **

Climbing Swimming Immobility

**

SIDE EFFECTS

Depression: Forced swim test (FST)

V e h i c l e n

• v

e l a n a l

• g

u e V e h i c l e n

• v

e l a n a l

• g

u e V e h i c l e n

• v

e l a n a l

• g

u e

50 100 150 200 250

Climbing Swimming Immobility

Time (s)

#1 C16 analogue C2 Analogue

SIDE EFFECTS

Anxiety: Light/Dark test

Anxiety

Treatment Time in light box (s)

vehicle Salvinorin A #2 C16 analogue #1 C16 analogue C2 analogue 50 100 150 200

**

Conclusions

Analogues of Salvinorin A hold promise for the development of anti-addiction pharmacotherapies

• All Longer acting
• Fewer side effects
• All have anti-cocaine effects (decrease drug–seeking)
• No sedative effects observed
• #1 C16 analogue has no pro-depressive effects or anxiety effects
• But shows aversion
• C2 analogue has no anxiety effects or aversion but has pro-depressive

effects

• #2 C16 analogue has highest efficacy in drug-seeking tests but side effects

need to be fully evaluated

ACKNOWLEDGEMENTS:

David Young Amy Ewald Aimee Culverhouse Nitin Kumar Bridget Simonson Aashish Morani

• Prof. Thomas Prisinzano

& Andrew Riley University of Kansas