OPEN Foundation

B. Kivell

Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents.

October 11, 2018 / New substances, Other subjects, Other substances, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum. We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 °C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.
Kivell, B., Paton, K., Kumar, N., Morani, A., Culverhouse, A., Shepherd, A., … & Prisinzano, T. (2018). Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents. Molecules, 23(10), 2602., 10.3390/molecules23102602
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“Quite a Profoundly Strange Experience”: An Analysis of the Experiences of Salvia divinorum Users

May 13, 2016 / Anthropology, Other disciplines, Other subjects, Papers, Publications, Salvia / Salvinorin A, Sociology / By / , ,

Abstract

Salvia divnorum (an intense hallucinogen) is currently illegal in New Zealand under the 2014 Psychoactive Substances Amendment Act. Despite this, there is a scarcity of research surrounding Salvia divinorum and its effects in a New Zealand context. To explore the experiences of Salvia divinorum users, an anonymous questionnaire was advertised through flyers placed in locations where young adults congregate. A total of 393 people took part in the online questionnaire in 2010-2011, while salvia was legally available in New Zealand; 167 respondents had used salvia. Thematic analysis was used to analyze the resulting open-ended questionnaire data and three key themes were identified: the effects of salvia; the importance of set and setting; salvia use and pleasure/not-pleasure. Recreational use of salvia was situated within a broader drug landscape, with participants being drug experienced and “drug wise” (Measham, Aldridge, and Parker 2001). Use of salvia also appeared to be intermittent, with its use referred to as a novel experience. Thus, the recent criminalization of salvia under the 2014 Act may see a significant decline in use as experienced drug users look elsewhere for novel drug experiences.

Hutton, F., Kivell, B., & Boyle, O. (2016). “Quite a Profoundly Strange Experience”: An Analysis of the Experiences of Salvia divinorum Users. Journal of Psychoactive Drugs, 1-8. http://dx.doi.org/10.1080/02791072.2016.1179376

Link to full text

"Quite a Profoundly Strange Experience": An Analysis of the Experiences of Salvia divinorum Users

May 13, 2016 / Anthropology, Other disciplines, Other subjects, Papers, Publications, Salvia / Salvinorin A, Sociology / By / , ,

Abstract

Salvia divnorum (an intense hallucinogen) is currently illegal in New Zealand under the 2014 Psychoactive Substances Amendment Act. Despite this, there is a scarcity of research surrounding Salvia divinorum and its effects in a New Zealand context. To explore the experiences of Salvia divinorum users, an anonymous questionnaire was advertised through flyers placed in locations where young adults congregate. A total of 393 people took part in the online questionnaire in 2010-2011, while salvia was legally available in New Zealand; 167 respondents had used salvia. Thematic analysis was used to analyze the resulting open-ended questionnaire data and three key themes were identified: the effects of salvia; the importance of set and setting; salvia use and pleasure/not-pleasure. Recreational use of salvia was situated within a broader drug landscape, with participants being drug experienced and “drug wise” (Measham, Aldridge, and Parker 2001). Use of salvia also appeared to be intermittent, with its use referred to as a novel experience. Thus, the recent criminalization of salvia under the 2014 Act may see a significant decline in use as experienced drug users look elsewhere for novel drug experiences.

Hutton, F., Kivell, B., & Boyle, O. (2016). “Quite a Profoundly Strange Experience”: An Analysis of the Experiences of Salvia divinorum Users. Journal of Psychoactive Drugs, 1-8. http://dx.doi.org/10.1080/02791072.2016.1179376

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Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues

December 26, 2014 / Addiction, Chemistry, Other subjects, Other substances, Papers, Psychopharmacology, Publications, Salvia / Salvinorin A / By / , , , , ,

Abstract

The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the κ-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other κ-opioid agonists.

Riley, A. P., Groer, C. E., Young, D., Ewald, A. W., Kivell, B. M., & Prisinzano, T. E. (2014). Synthesis and Kappa Opioid Receptor Activity of Furan-Substituted Salvinorin A Analogues. Journal of medicinal chemistry. https://dx.doi.org/10.1021/jm501521d
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30 April - Q&A with Rick Strassman

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