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

Preclinical development of novel kappa opioid compounds for the treatment of drug-addiction Dr Bronwyn Kivell Centre for Biodiscovery Victoria University of Wellington

Addiction and Reward ABUSE Craving Withdrawal > No approved pharmacotherapies for treatment of psychostimulant addiction

Kappa opioid systems & Addiction

Kappa opioids Co-Localization of regulate Dopamine KOPr and DAT levels * Wild-type 300 Heterozygote * Knock-Out * 200 DA 100 0 Saline 5.0 10.0 15.0 Cocaine Dose (mg/kg) Chefer et al., J Neuroscience (2005) Svingos et al ., 2001

ANTI-COCAINE EFFECTS Cocaine/ KOPr Agonist Interactions Drug-primed reinstatement model  KOPr Agonists Exert Cocaine self- admin ‘ Cocaine- Antagonist’ Like Effects in Animal Models of Extinction (saline) Drug-Seeking Reinstatement  Attenuates i.v. cocaine self- > KOPr treatment administration Reinstatement > Drug-prime - Test  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)

C-16 Salvia divinorum Modified C16 analogues C-2 Modified analogues Modified C2 analogue Salvinorin A EC 50 : 0.030 nM

ANTI-ADDICTION EFFECTS Cocaine prime-induced reinstatement 150 400 400 300 300 Responses 100 Responses Responses * * 200 200 ** 50 ** ** 100 100 0 0 0 Control 0.1 0.3 1.0 Baseline Extinction Control 0.1 0.3 0.3 1 Control Treatment Treatment Treatment #2 #1 C2 Analogue C16 analogue C16 analogue

LONGER DURATION OF ACTION Tail flick latency *** 40 ** #1 C16 analogue (1 mg/kg) *** 30 *** * SalA (1 mg/Kg) Tail * Vehicle * %MPE 20 withdrawal 10 0 assay 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 Time (min) -10 ^^^^ 40 **** C2 analogue (1 mg/Kg) 30 SalA (1 mg/Kg) # *** Veh # 20 %MPE * # 10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 -10 Time (min)

SIDE EFFECTS Spontaneous locomotion Sedation Sedation: Locomotor activity 2000 2000 2000 Total ambulatory counts Total Ambulatory Counts Total ambulatory counts 1500 1500 1500 1000 1000 1000 500 500 500 0 0 0 e e e e Vehicle Novel analogue l u l c u g c i g h i o h o e l e a l V a n V n a a l e l e v v o o N N #2 #1 C2 Analogue C16 analogue C16 analogue

SIDE EFFECTS Aversion: Conditioned place aversion 80 Time in paired chamber (%) 80 Time spent in chamber A * Pre Pre-test post Post-test 60 60 (%) 40 40 20 20 0 0 Novel analogue vehicle e e l u c g i h o e l a V n a l e v o N #1 C2 Analogue C16 analogue

SIDE EFFECTS Depression: Forced swim test (FST) Climbing Swimming Immobility Climbing 250 Swimming Immobility 250 ** 200 200 Time (s) 150 Time (s) 150 100 100 ** ** 50 50 0 0 Vehicle novel analogue Vehicle novel analogue Vehicle novel analogue e e e e e e l u l u l u c c c g g g i i i h h h o o o e e e l l l a a a V V V n n n a a a l l l e e e v v v o o o n n n #1 C2 Analogue C16 analogue

SIDE EFFECTS Anxiety: Light/Dark test Anxiety 200 Time in light box (s) 150 100 ** 50 0 vehicle Salvinorin A #2 C16 analogue #1 C16 analogue C2 analogue Treatment

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