Salvinorin A, a kappa-opioid receptor agonist hallucinogen : pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders

Eduardo R. Butelman and Mary Jeanne Kreek

Frontiers in Pharmacology, 2015

doi: 10.3389/fphar.2015.00190

Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A-containing products have undergone frequent nonmedical use. KOPr/dynorphin systems in the brain are known to be powerful countermodulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and chemical reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A.

Keywords : kappa-opioid receptor, dynorphins, salvinorin A, Salvia divinorum, depression, addiction

 

Salvinorin A

Salvinorin A (derived from the ethnomedical plant Salvia divinorum) is a powerful hallucinogen
in humans, and is a selective, high efficacy agonist at kappa-opioid receptors (KOPr; Roth et al.,
2002; Chavkin et al., 2004). Salvinorin A is unique for several reasons, which include: (a) it is the
first plant-derived ligand with high selectivity for KOPr over other receptors, including mu-opioid
receptor (MOPr) (the target of opioid alkaloids, such as morphine), (b) it is structurally unrelated
to any known opioid receptor ligand, and is a non-nitrogenous diterpene, (c) it is pharmacologically
and mechanistically distinct from other known hallucinogens in humans (e.g., classic serotonergic
hallucinogens, which are primarily 5HT2A agonists), (d) it is the only selective KOPr ligand to
become relatively widely available outside research or medical settings. This is also related to its
diffusion through the internet and other commercial outlets, due to its complex legal status across
jurisdictions.

The KOPr System and its Endogenous Agonist Neuropeptides, the Dynorphins

KOPr receptors are members of the opioid receptor 7- transmembrane domain (7TM) G-protein coupled receptor (GPCR) superfamily,coupled primarily to Gi/o proteins that inhibit actions of adenylyl cyclase, and also activate alternate down stream pathways, including b-arrestin-mediated pathways and ERK/MAPkinase pathways (Dhawan et al., 1996; Bruchas and Chavkin, 2010; Zhou et al., 2013a). The endogenous KOPr agonists are the dynorphin neuropeptides, encoded by gene PDYN in humans (Chavkin and Goldstein, 1981; Chavkin, 2012). KOPr and the dynorphins are located in many parts oft he central nervous system (CNS; and also in the peripheral nervous system). In the CNS,KOPr/dynorphin systems are prominent in the dorsal and ventral striatum (e.g., caudate-putamen and Nucleus accumbens, respectively), several cortical areas, and limbic areas including hippocampus and amygdala, as well as hypothalamus and spinal cord (Mansour et al., 1988; Spangler et al., 1993; Unterwald et al., 1994; Simonin et al., 1995; Mathieu- Kia et al., 2001). Thus, this receptor/ligand system mediates diverse behavioral functions, including mediation of reward and aversion, mood, anxiety, stress-responsivity, memory and higher cognitive functions, as well as neuroendocrine effects and pain/analgesia. KOPr/dynorphin systems are co-localized in most major dopaminergic areas in the CNS. KOPr activation, by exogenous ligands including salvinorin A, or by dynorphins, tends to result in a decrease in dopaminergic activation in dorsal and ventral striatum(Di Chiara and Imperato, 1988; Spanagel et al., 1990; Zhang et al., 2004, 2005; Carlezon et al., 2006; i.e., an effect opposite to that of diverse drugs of abuse, including cocaine, otherpsychostimulants and MOPr agonists).

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