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| Formula | C28H30O8 |
| Molar mass | 494.540 g·mol−1 |
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Herkinorin is anopioidanalgesic that is ananalogue of the natural productsalvinorin A. It was discovered in 2005 during structure-activity relationship studies intoneoclerodanediterpenes, the family of chemical compounds of which salvinorin A is a member.[1]
Unlike salvinorin A, which is a selectiveκ-opioid receptoragonist with no significantμ-opioid receptor affinity, herkinorin is predominantly a μ-opioid receptor agonist. Compared to salvinorin A, herkinorin has 47× loweraffinity for κ-opioid receptors (Ki = 90 nM vs Ki = 1.9 nM), and at least 25× higher affinity for μ-opioid receptors (Ki = 12 nM vs Ki >1000 nM), where it acts as a full agonist (IC50 = 0.5 μM, Emax = 130% vsDAMGO).[2][3] Herkinorin is asemi-synthetic compound, made fromsalvinorin B, which is most conveniently made from salvinorin A bydeacetylation, since, while both salvinorin A and salvinorin B are found in the plantSalvia divinorum, salvinorin A is present in larger quantities.[4]
A study in primates showed it to actperipherally as both a μ- and κ-opioid receptor agonist, with a fast onset of action. The study did not find any evidence ofcentral activity in primates and questions whether herkinorin's effects are due entirely to peripheral binding.[5] Unlike most μ-opioid receptor agonists, herkinorin does not promote the recruitment ofβ-arrestin 2 to the intracellular domain of the μ-opioid receptor, or inducereceptor internalization.[6] This means that herkinorin may not producetolerance anddependence in the same way as other opioids, although some development of tolerance through other mechanisms has been observed,[7] and some other analogues related to herkinorin can recruit β-arrestins.[8]
