The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal
Bandβ-tetrahydropyran Sal B, have anti-cocaine properties
with minimal side effects
Amy W.M. Ewald
Peter J. Bosch
Rachel Saylor Crowley
Thomas E. Prisinzano
Bronwyn M. Kivell
Received: 31 May 2016 /Accepted: 5 May 2017 /Published online: 23 May 2017
Springer-Verlag Berlin Heidelberg 2017
Rationale Kappa-opioid receptor (KOPr) agonists have
pre-clinical anti-cocaine and analgesic effects. However, side
effects including sedation, dysphoria, aversion, anxiety and
depression limit their therapeutic development. The unique
structure of salvinorin A has been used to develop longer
acting KOPr agonists.
Objectives We evaluate two novel C-2 analogues of
salvinorin A, ethoxymethyl ether Sal B (EOM Sal B) and
β-tetrahydropyran Sal B (β-THP Sal B) alongside U50,488
for their ability to modulate cocaine-induced behaviours and
side effects, pre-clinically.
Methods Anti-cocaine properties of EOM Sal B were evalu-
ated using the reinstatement model of drug seeking in
self-administering rats. EOM Sal B and β-THP Sal B were
evaluated for effects on cocaine-induced hyperactivity, spon-
taneous locomotor activity and sucrose self-administration.
EOM Sal B and β-THP Sal B were evaluated for aversive,
anxiogenic and depressive-like effects using conditioned
place aversion (CPA), elevated plus maze (EPM) and forced
swim tests (FSTs), respectively.
Results EOM Sal B (0.1, 0.3 mg/kg, intraperitoneally (i.p.))
dose dependently attenuated drug seeking, and EOM Sal B
(0.1 mg/kg, i.p.) and β-THP Sal B (1 mg/kg, i.p.) attenuated
cocaine-induced hyperactivity. No effects on locomotor
activity, open arm times (EPM) or swimming behaviours
(FST) were seen with EOM (0.1 or 0.3 mg/kg, i.p.) or
β-THP Sal B (1 or 2 mg/kg, i.p.). However, β-THP Sal B
decreased time spent in the drug-paired chamber.
Conclusion EOM Sal B is more potent than Sal A and β-THP
Sal B in reducing drug-seeking behaviour with fewer side
effects. EOM Sal B showed no effects on sucrose
self-administration (0.1 mg/kg), locomotor, depressive-like,
aversive-like or anxiolytic effects.
Keywords Salvinorin A
Kappa-opioid receptor (KOPr) agonists have well-established
anti-reward and cocaine antagonistic actions in pre-clinical
models of drug use (Glick et al. 1998; Morani et al. 2009;
Morani et al. 2012; Schenk et al. 1999). These effects have
been attributed to their ability to decrease dopamine (DA)
release (Ebner et al. 2010) and increase DA reuptake via reg-
ulation of the dopamine transporter (DAT) (Kivell et al. 2014).
Unfortunately, activation of KOPrs by traditional
arylacetamide agonists such as U50,488 and U69,593 also
causes side effects that include sedation (Gallantine and
Meert 2008), aversion (Land et al. 2009), anxiety (Gillett
et al. 2013) and depression (Mague et al. 2003), effects that
have limited their use clinically (Walsh et al. 2001a,b).
Salvinorin A (Sal A) is a structurally unique KOPr agonist
with a non-nitrogenous structure (Prisinzano 2005;Rothetal.
2002), isolated from the plant Salvia divinorum and is known
to produce hallucinogenic effects in humans (MacLean et al.
* Bronwyn M. Kivell
School of Biological Sciences, Centre for Biodiscovery, Victoria
University of Wellington, Wellington, New Zealand
Present address: Department of Biology, University of Iowa, Iowa
City, IA 52242, USA
Department of Medicinal Chemistry, School of Pharmacy, University
of Kansas, Lawrence, KS, USA
Psychopharmacology (2017) 234:2499–2514