Herkinorin is an

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

that is an analogue of the natural product salvinorin A. It was discovered in 2005 during structure-activity relationship studies into

neoclerodane Clerodane diterpenes, sometimes referred to as clerodane diterpenoids, are a large group of secondary metabolites that have been isolated from several hundreds of different plant species, as well as fungi, bacteria and marine sponges. They are bicy ...

diterpenes Diterpenes are a class of chemical compounds composed of four isoprene units, often with the molecular formula C20H32. They are biosynthesized by plants, animals and fungi via the HMG-CoA reductase pathway, with geranylgeranyl pyrophosphate bei ...

, the family of chemical compounds of which salvinorin A is a member. Unlike salvinorin A, which is a selective

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind ...

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

with no significant

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

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). Herkinorin is a semi-synthetic compound, made from

salvinorin B Salvinorin A is the main active psychotropic molecule in ''Salvia divinorum''. Salvinorin A is considered a dissociative hallucinogen. It is structurally distinct from other naturally occurring hallucinogens (such as DMT, psilocybin, and ...

, which is most conveniently made from salvinorin A by

deacetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...

, since, while both salvinorin A and salvinorin B are found in the plant ''

Salvia divinorum ''Salvia divinorum'' (Latin: "sage of the diviners"; also called ska maría pastora, seer's sage, yerba de la pastora, magic mint or simply salvia) is a plant species with transient psychoactive properties when its leaves are consumed by che ...

'', salvinorin A is present in larger quantities. 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 Central is an adjective usually referring to being in the center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central Africa, a region in the centre of Africa continent, also known a ...

activity in primates and questions whether herkinorin's effects are due entirely to peripheral binding. 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. This means that herkinorin may not produce

tolerance Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...

and dependence in the same way as other opioids, although some development of tolerance through other mechanisms has been observed, and some other analogues related to herkinorin can recruit β- arrestins.

References

{{Opioidergics Benzoate esters 3-Furyl compounds Kappa-opioid receptor agonists Methyl esters Peripherally selective drugs Semisynthetic opioids Lactones

See also

References