Herkinorin

Herkinorin is an opioid 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]

Drug classμ-Opioid receptor agonist; κ-Opioid receptor agonist

ATC code

• None

Legal status

• Legal/Uncontrolled

CAS Number

• 862073-77-6 ^Y

Quick facts Clinical data, Drug class ...

Herkinorin

Clinical data
Drug class	μ-Opioid receptor agonist; κ-Opioid receptor agonist
ATC code	None
Legal status
Legal status	Legal/Uncontrolled
Identifiers
IUPAC name methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-9-benzoyloxy-2-(furan-3-yl)-6a,10b-dimethyl-4,10-dioxo-2,4a,5,6,7,8,9,10a-octahydro-1H-benzo[f]isochromene-7-carboxylate
CAS Number	862073-77-6 Y
PubChem CID	11431898
ChemSpider	9606773 Y
UNII	5XN29VGR24
ChEMBL	ChEMBL363324 Y
CompTox Dashboard (EPA)	DTXSID30235444
Chemical and physical data
Formula	C28H30O8
Molar mass	494.540 g·mol−1
3D model (JSmol)	Interactive image
SMILES 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 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 Y Key:PYDQMXRFUVDCHC-XAGHGKQISA-N Y
NY (what is this?)  (verify)

Close

Unlike salvinorin A, which is a selective κ-opioid receptor agonist 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 (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]