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 us ...
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
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 ...
. 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 being ...
, 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 op ...
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 ago ...
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
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Partn ...
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 (IC
50 = 0.5 μM, E
max = 130% vs
DAMGO
DAMGO ( D-Ala2,_''N''-MePhe4,_Gly-ol.html" ;"title="small>D-Ala2, ''N''-MePhe4, Gly-ol">small>D-Ala2, ''N''-MePhe4, Gly-olenkephalin) is a synthetic opioid peptide with high μ-opioid receptor specificity. It was synthesized as a biologically stab ...
). Herkinorin is a
semi-synthetic
Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds with ...
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 opposit ...
, 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 as ...
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
Beta-arrestin-2, also known as arrestin beta-2, is an intracellular protein that in humans is encoded by the ''ARRB2'' gene.
Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G prot ...
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.
See also
*
Kurkinorin
*
Salvinorin B methoxymethyl ether
Salvinorin B methoxymethyl ether (2-''O''-methoxymethylsalvinorin B) is a semi-synthetic analogue of the natural product salvinorin A used in scientific research. It has a longer duration of action of around 2–3 hours, compared to less than 30 ...
*
RB-64
RB-64 (22-thiocyanatosalvinorin A) is a semi-synthetic salvinorin A, salvinorin derivative and a κ-opioid receptor (KOR) agonist which is used in scientific research. Its most remarkable property is its functional selectivity for G protein versu ...
References
{{Opioidergics
Benzoate esters
3-Furyl compounds
Kappa-opioid receptor agonists
Methyl esters
Peripherally selective drugs
Semisynthetic opioids
Lactones