Herkinorin

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Herkinorin
Herkinorin.svg
Systematic (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
Clinical data
Legal status
  • Legal/Uncontrolled
Identifiers
ATC code none
PubChem CID: 11431898
ChemSpider 9606773 YesY
ChEMBL CHEMBL363324 YesY
Chemical data
Formula C28H30O8
Molecular mass 494.55 g/mol
  • O=C(OC)[C@H]3[C@@]4(CC[C@H]5C(=O)O[C@H](c1ccoc1)C[C@@]5([C@H]4C(=O)[C@@H](OC(=O)c2ccccc2)C3)C)C
  • InChI=1S/C28H30O8/c1-27-11-9-18-26(32)36-21(17-10-12-34-15-17)14-28(18,2)23(27)22(29)20(13-19(27)25(31)33-3)35-24(30)16-7-5-4-6-8-16/h4-8,10,12,15,18-21,23H,9,11,13-14H2,1-3H3/t18-,19-,20-,21-,23-,27-,28-/m0/s1 YesY
  • Key:PYDQMXRFUVDCHC-XAGHGKQISA-N YesY
  (verify)

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 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.[2][3] Herkinorin is a semi-synthetic compound, made from Salvinorin B, which is most conveniently made from Salvinorin A by deacetylation, as 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 as both a peripherally active μ and κ 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 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

References

  1. ↑ [1] 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
  2. ↑ [2] 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
  3. ↑ [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 and Medicinal Chemistry Letters. 2007 Nov 15;17(22):6111-5. PMID 17904842
  4. ↑ [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 and Medicinal Chemistry Letters. 2004; 14: 5099-5102. PMID 15380207
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ [5] 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
  7. ↑ [6] 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
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.


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