Salvinorin A

Pharmacodynamics

Research has shown that salvinorin A is a potent κ-opioid receptor (KOR) agonist (K_i = 2.4 nM, EC₅₀ = 1.8 nM).^[10] It has a high affinity for the receptor, indicated by the low dissociation constant of 1.0 nanomolar (nM).^[15] It shows atypical properties as an agonist of the KOR relative to other KOR agonists.^[16] In addition to its KOR agonism, salvinorin A has been found to act as a dopamine D₂ receptor partial agonist, with an affinity of 5–10 nM, an intrinsic activity of 40–60%, and an EC₅₀ of 48 nM.^[17] As such, the dopamine D₂ receptor might also play a role in its effects.^[17]

Salvinorin A has no action at the 5-HT_2A serotonin receptor, the principal molecular target responsible for the actions of 'classical' psychedelics such as LSD and mescaline.^[9][18] Salvinorin A has also been shown to have effect on cannabinoid CB1 receptors.^[19] It significantly increases prolactin and inconsistently increases cortisol.^[20] It causes dysphoria by stopping release of dopamine in the striatum.^[21] Salvinorin A increases activity of DAT while decreasing activity of SERT.^[21]

Salvinorin A is capable of inhibiting excess intestinal motility (e.g. diarrhea), through its potent κ-opioid-activating effects. The mechanism of action for salvinorin A on ileal tissue has been described as 'prejunctional', as it was able to modify electrically induced contractions, but not those of exogenous acetylcholine.^[22] A pharmacologically important aspect of the contraction-reducing properties of ingested salvinorin A on gut tissue is that it is only pharmacologically active on inflamed and not normal tissue, thus reducing possible side-effects.^[23]

Pharmacokinetics

Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of administration must be used for better absorption. It is absorbed by oral mucosa.^[24] It has a half-life of around 8 minutes in non-human primates.^[25]

Solubility

Salvinorin A is soluble in organic solvents such as ethanol and acetone, but not especially so in water.^[26]

Chemical synthesis

The chemical synthesis of salvinorin A has been described.^[1] A total asymmetric synthesis of salvinorin A, which relies on a transannular Michael reaction cascade to construct the ring system, was achieved as a 4.5% overall yield over 30 steps,^[27] then revised using 24 steps to yield salvinorin A in 0.15% yield.^[28] An approach to the trans-decalin ring system of salvinorin A used an intramolecular Diels-Alder reaction/Tsuji allylation strategy,^[29] and a total synthesis of salvinorin A was achieved using the intramolecular Diels-Alder / Tsuji allylation approach, combined with an asymmetric late-stage addition of the furan moiety.^[30]

Detection in urine

Researchers found that humans who smoked 580 μg of the pure drug had urine salvinorin A concentrations of 2.4–10.9 μg/L during the first hour; the levels fell below the detection limit by 1.5 hours after smoking.^[31]

Associated compounds

Salvinorin A is one of several structurally related salvinorins found in the Salvia divinorum plant. Salvinorin A is the only naturally occurring salvinorin that is known to be psychoactive.^[32] Salvinorin A can be synthesized from salvinorin B by acetylation, and de-acetylated salvinorin A becomes analog to salvinorin B.^[33]

Research has produced a number of semi-synthetic compounds. Most derivatives are selective kappa opioid agonists as with salvinorin A, although some are even more potent, with the most potent compound salvinorin B ethoxymethyl ether being ten times stronger than salvinorin A. Some derivatives, such as herkinorin, reduce kappa opioid action and instead act as mu opioid agonists.^{[34][35][36][37]}

The synthetic derivative RB-64 is notable because of its functional selectivity and potency.^[38] Salvinorin B methoxymethyl ether is seven times more potent than salvinorin A at KOPr in GTP-γS assays.^[39]

Biosynthesis

The biogenic origin of salvinorin A synthesis has been elucidated using nuclear magnetic resonance and ESI-MS analysis of incorporated precursors labeled with stable isotopes of carbon (carbon-13 ¹³C) and hydrogen (deuterium ²H). It "is biosynthesized via the 1-deoxy-d-xylulose-5-phosphate pathway", rather than the classic mevalonate pathway, consistent with the common plastidial localization of diterpenoid metabolism.^[42]

Terpenoids are biosynthesized from two 5-carbon precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). The NMR and MS study by Zjawiony suggested that the biosynthesis of salvinorin A proceeds via the 1-deoxy-d-xylulose-5-phosphate pathway. In the deoxyxylulose phosphate pathway, D-glyceraldehyde 3-phosphate and pyruvate, the intermediates of the glycolysis, are converted into 1-deoxy-D-xylulose 5-phosphate via decarboxylation. Subsequent reduction with NADPH generates 2C-methyl-D-erythritol 2,4-cyclodiphosphate, via the intermediates 4-diphosphocytidyl-2-C-methyl-D-erythritol and 4-diphosphocytidyl-2c-methyl-d-erythritol-2-phosphate, which then lead to IPP and DMAPP.

Subsequent addition of three 5-carbon IPP units to a single 5-carbon DMAPP unit generates the 20-carbon central precursor, geranylgeranyl diphosphate (GGPP). Bicyclization of GGPP by the class II diterpene synthase, ent-clerodienyl diphosphate synthase (SdCPS2^[43]), produces a labdanyl diphosphate carbocation, which is subsequently rearranged through a sequence of 1,2-hydride and methyl shifts to form the ent-clerodienyl diphosphate intermediate.^[44] SdCPS2 catalyzes the first committed reaction in the biosynthesis of salvinorin A by producing its characteristic clerodane scaffold. A series of oxygenation, acylation and methylation reactions is then required to complete the biosynthesis of salvinorin A.^[43]

Similar to many plant-derived psychoactive compounds, salvinorin A is excreted via peltate glandular trichomes, which reside external to the epidermis.^[45][46]

Legal status

Salvinorin A is sometimes regulated together with its host, Salvia divinorum, due to its psychoactive and analgesic effects.