Herkinorin is an opioidanalgesic that is an analogue of the natural product salvinorin A. It was discovered in 2005 during structure-activity relationship studies into neoclerodanediterpenes, the family of chemical compounds of which salvinorin A is a member.[1]
Unlike salvinorin A, which is a selective κ-opioid receptoragonist with no significant μ-opioid receptor affinity, herkinorin is predominantly a μ-opioid receptor agonist. Compared to salvinorin A, herkinorin has 47× lower affinity 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% vs DAMGO).[2][3] Herkinorin is a semi-synthetic compound, made from salvinorin B, which is most conveniently made from salvinorin A by deacetylation, since, while both salvinorin A and salvinorin B are found in the plant Salvia divinorum, salvinorin A is present in larger quantities.[4]
A study in primates showed it to act peripherally as both a μ- and κ-opioid receptor agonist, with a fast onset of action. The study did not find any evidence of central 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 of β-arrestin 2 to the intracellular domain of the μ-opioid receptor, or induce receptor internalization.[6] This means that herkinorin may not produce tolerance and dependence 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]
^Harding WW, Tidgewell K, Byrd N, Cobb H, Dersch CM, Butelman ER, et al. (July 2005). "Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands". Journal of Medicinal Chemistry. 48 (15): 4765–71. doi:10.1021/jm048963m. PMID16033256.
^Tidgewell K, Harding WW, Lozama A, Cobb H, Shah K, Kannan P, et al. (June 2006). "Synthesis of salvinorin A analogues as opioid receptor probes". Journal of Natural Products. 69 (6): 914–8. CiteSeerX10.1.1.693.6345. doi:10.1021/np060094b. PMID16792410.
^Tidgewell K, Harding WW, Schmidt M, Holden KG, Murry DJ, Prisinzano TE (October 2004). "A facile method for the preparation of deuterium labeled salvinorin A: synthesis of [2,2,2-2H3]-salvinorin A". Bioorganic & Medicinal Chemistry Letters. 14 (20): 5099–102. doi:10.1016/j.bmcl.2004.07.081. PMID15380207.
