Herkinorin

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IUPAC_name = (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(Benzoyloxy)-2-(3-furanyl)dodecahydro -6a,10b-dimethyl-4,10-dioxo-2H-naphtho- [2,1-c] pyran-7-carboxylic acid methyl ester

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synonyms = Herkinorin
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C = 28 | H = 30 | O = 8
molecular_weight = 494.55 g/mol
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legal_status = Legal
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Herkinorin is an opioid analgesic that is an analogue of the natural product Salvinorin A. It was discovered in 2005 during structure-activity relationship studies into neoclerodane diterpenes, the family of chemical compounds of which Salvinorin A is a member. [ [http://dx.doi.org/10.1021/jm048963m] Harding WW, Tidgewell K, Byrd N, Cobb H, Dersch CM, Butelman ER, Rothman RB, Prisinzano TE. "Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands." "Journal of Medicinal Chemistry". 2005 Jul 28;48(15):4765-71. PMID 16033256]

Unlike Salvinorin A which is a selective κ-opioid agonist with no significant μ-opioid receptor affinity, herkinorin is a μ-opioid agonist with more than 100x higher μ-opioid affinity and 50x lower κ-opioid affinity compared to Salvinorin A. [ [http://dx.doi.org/10.1021/np060094b] Tidgewell K, Harding WW, Lozama A, Cobb H, Shah K, Kannan P, Dersch CM, Parrish D, Deschamps JR, Rothman RB, Prisinzano TE. "Synthesis of salvinorin A analogues as opioid receptor probes." "Journal of Natural Products". 2006 Jun;69(6):914-8. PMID 16792410] [ [http://dx.doi.org/10.1016/j.bmcl.2007.09.050] Holden KG, Tidgewell K, Marquam A, Rothman RB, Navarro H, Prisinzano TE. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Exploration of the 1-position. "Bioorganic and Medicinal Chemistry Letters". 2007 Nov 15;17(22):6111-5. PMID 17904842] Herkinorin is a semi-synthetic compound made from Salvinorin B, which is found alongside Salvinorin A or made from Salvinorin A, which is extracted from the plant "Salvia divinorum", by deacetylation. [ [http://dx.doi.org/10.1016/j.bmcl.2004.07.081] Tidgewell K, Harding WW, Schmidt M, Holden KG, Murry DJ, Prisinzano TE. "A facile method for the preparation of deuterium labeled salvinorin A: synthesis of [2,2,2-2H3] -salvinorin A." "Bioorganic and Medicinal Chemistry Letters". 2004; 14: 5099-5102. PMID 15380207]

Since it is highly selective for the mu isoform of the opioid receptor, it is likely that herkinorin will be found to produce similar effects to other μ-opioid selective agonists in vivo, such as analgesia and sedation, along with side effects such as nausea, itching, vomiting and respiratory depression which may be harmful or fatal. However unlike most μ-opioid agonists, herkinorin does not promote the recruitment of β-arrestin-2 to the intracellular domain of the μ-opioid receptor, or induce receptor internalisation. [ [http://dx.doi.org/10.1124/mol.106.028258] Groer CE, Tidgewell K, Moyer RA, Harding WW, Rothman RB, Prisinzano TE, Bohn LM. "An opioid agonist that does not induce μ-opioid receptor--arrestin interactions or receptor internalization." "Molecular Pharmacology". 2007 Feb;71(2):549-57. PMID 17090705] 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. [ [http://dx.doi.org/10.1002/syn.20356] Xu H, Partilla JS, Wang X, Rutherford JM, Tidgewell K, Prisinzano TE, Bohn LM, Rothman RB. "A comparison of noninternalizing (herkinorin) and internalizing (DAMGO) mu-opioid agonists on cellular markers related to opioid tolerance and dependence." "Synapse". 2007 Mar;61(3):166-75. PMID 17152090]

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