Herkinorin Explained

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.^[1]

Unlike salvinorin A, which is a selective μ-opioid receptor agonist with no significant κ-opioid receptor affinity, herkinorin is predominantly a μ-opioid receptor agonist. Compared to salvinorin A, herkinorin has 47× lower affinity for κ-opioid receptors (K_i ＝ 90 nM vs K_i ＝ 1.9 nM), and at least 25× higher affinity for μ-opioid receptors (K_i ＝ 12 nM vs K_i >1000 nM), where it acts as a full agonist (IC₅₀ ＝ 0.5 μM, E_max ＝ 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]

See also

• Kurkinorin
• Salvinorin B methoxymethyl ether
• RB-64

Notes and References

1. Harding WW, Tidgewell K, Byrd N, Cobb H, Dersch CM, Butelman ER, Rothman RB, Prisinzano TE . 6 . Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands . Journal of Medicinal Chemistry . 48 . 15 . 4765–71 . July 2005 . 16033256 . 10.1021/jm048963m .
2. Tidgewell K, Harding WW, Lozama A, Cobb H, Shah K, Kannan P, Dersch CM, Parrish D, Deschamps JR, Rothman RB, Prisinzano TE . 6 . Synthesis of salvinorin A analogues as opioid receptor probes . Journal of Natural Products . 69 . 6 . 914–8 . June 2006 . 16792410 . 10.1021/np060094b . 10.1.1.693.6345 .
3. 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 & Medicinal Chemistry Letters . 17 . 22 . 6111–5 . November 2007 . 17904842 . 2111044 . 10.1016/j.bmcl.2007.09.050 .
4. 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 & Medicinal Chemistry Letters . 14 . 20 . 5099–102 . October 2004 . 15380207 . 10.1016/j.bmcl.2004.07.081 .
5. Butelman ER, Rus S, Simpson DS, Wolf A, Prisinzano TE, Kreek MJ . The effects of herkinorin, the first mu-selective ligand from a salvinorin A-derived scaffold, in a neuroendocrine biomarker assay in nonhuman primates . The Journal of Pharmacology and Experimental Therapeutics . 327 . 1 . 154–60 . October 2008 . 18593955 . 2614932 . 10.1124/jpet.108.140079 .
6. Groer CE, Tidgewell K, Moyer RA, Harding WW, Rothman RB, Prisinzano TE, Bohn LM . An opioid agonist that does not induce mu-opioid receptor--arrestin interactions or receptor internalization . Molecular Pharmacology . 71 . 2 . 549–57 . February 2007 . 17090705 . 3926195 . 10.1124/mol.106.028258 .
7. Xu H, Partilla JS, Wang X, Rutherford JM, Tidgewell K, Prisinzano TE, Bohn LM, Rothman RB . 6 . A comparison of noninternalizing (herkinorin) and internalizing (DAMGO) mu-opioid agonists on cellular markers related to opioid tolerance and dependence . Synapse . 61 . 3 . 166–75 . March 2007 . 17152090 . 10.1002/syn.20356 . 23678472 . Submitted manuscript .
8. Tidgewell K, Groer CE, Harding WW, Lozama A, Schmidt M, Marquam A, Hiemstra J, Partilla JS, Dersch CM, Rothman RB, Bohn LM, Prisinzano TE . 6 . Herkinorin analogues with differential beta-arrestin-2 interactions . Journal of Medicinal Chemistry . 51 . 8 . 2421–31 . April 2008 . 18380425 . 2494883 . 10.1021/jm701162g .