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The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and β-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects

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Abstract

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 evaluated 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, spontaneous 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.

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Acknowledgements

Funding was provided by the Neurological Foundation of New Zealand and the Health Research Council of New Zealand (to BMK), DA018151 (to TEP), GM008545 (to RSC) and an AFPE Pre-Doctoral Fellowship in Pharmaceutical Sciences (to RSC). A Postgraduate Research Scholarship was provided by Victoria University of Wellington (to AE). We would like to acknowledge Andrew Biggerstaff, Kelly Paton and Stephen Mathew for technical assistance.

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  1. Peter J. Bosch

    Present address: Department of Biology, University of Iowa, Iowa City, IA, 52242, USA

Authors and Affiliations

  1. School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand

    Amy W.M. Ewald, Peter J. Bosch, Aimee Culverhouse & Bronwyn M. Kivell

  2. Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS, USA

    Rachel Saylor Crowley, Benjamin Neuenswander & Thomas E. Prisinzano

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  1. Amy W.M. Ewald
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All animal use and procedures were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals and approved by the Victoria University of Wellington Animal Ethics Committee, Wellington, New Zealand.

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Ewald, A.W., Bosch, P.J., Culverhouse, A. et al. The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and β-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects. Psychopharmacology 234, 2499–2514 (2017). https://doi.org/10.1007/s00213-017-4637-2

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