Abstract
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 non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory 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.
Highlights
(c) Exposure to stress or to drugs of abuse results in an upregulation in KOPr/dynorphin activity, and this may underlie, in part, neurobiological and behavioral effects observed in these conditions
KOPr/dynorphin systems are present in areas involved in mood, anxiety and stress processing
(f) Salvinorin A is a novel scaffold for medicinal chemistry approaches, with the goal of generating novel compounds with pharmacotherapeutic potential, in neuropsychiatric diseases, including specific addictions
Summary
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 related to its diffusion through the internet and other commercial outlets, due to its complex legal status across jurisdictions
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