κ-Opioid receptor agonist

κ-Opioid receptor agonist
Drug class
Salvinorin A, a well-known KOR agonist found in Salvia divinorum and a hallucinogen
Class identifiers
Synonymskappa-Opioid receptor agonist; KOR agonist; Kappa agonist; Dysdelic; Salvinoid
UseAs hallucinogens or entheogens, as analgesics for pain, to treat pruritus (itch), and treatment of alcoholism
Mechanism of actionκ-Opioid receptor agonism
Biological targetκ-Opioid receptor
Chemical classSalvinorins; Benzomorphans or benzazocines; Morphinans; Peptides; Others
Legal status
In Wikidata

A κ-opioid receptor agonist, or simply KOR agonist or kappa agonist, is a drug which acts as an agonist of the κ-opioid receptor (KOR), the target of the endogenous dynorphin peptides such as dynorphin A and one of several types of opioid receptors.[1][2] They can variably produce hallucinogenic effects,[3] pro-depressive and dysphoric effects,[1][4] sedation,[1] analgesic effects,[5][6] antipruritic (anti-itch) effects,[7][8][9] and anti-addictive effects,[10] among others.[1] Due to their various effects, KOR agonists are used for a variety of medical uses and for other purposes.[1][4][3][11]

Salvinorin A is a highly potent and selective KOR agonist and hallucinogen found in Salvia divinorum (diviner's sage) which has been used as an entheogen by the Mazatec people of Mexico and as a recreational drug elsewhere.[3] The psychoactive and other effects of salvinorin A have been evaluated in clinical studies.[12][13][14][15][16][17] The non-selective opioid receptor antagonist naltrexone blocks the effects of salvinorin A.[17] Synthetic analogues with greater potency and/or duration include salvinorin B methoxymethyl ether (2-MMSB) and salvinorin B ethoxymethyl ether (2-EMSB).[11][18][19][20] The irreversible G protein-biased agonist RB-64 (22-thiocyanatosalvinorin A) has unknown psychoactivity.[21][22]

Nalorphine (N-allylnormorphine; Lethidrone; Nalline) was an early opioid antagonist used to reverse opioid overdose which acts as a dual μ-opioid receptor (MOR) agonist–antagonist and KOR agonist and was superseded by other drugs like naloxone due to producing dysphoria and hallucinogenic effects among other drawbacks.[23][24] Nalmefene (Revex, others) is a dual MOR antagonist and KOR lower-efficacy partial agonist which is used in the treatment of opioid overdose and alcoholism.[25][26][27]

Certain benzazocine or benzomorphan opioid analgesics like pentazocine (Talwin) and phenazocine (Prinadol, Narphen) act as dual KOR agonists and MOR agonists or antagonists and can produce hallucinogenic effects and dysphoria due to their KOR agonism.[28][29] Pentazocine has also been studied and reported to be effective in treating mania in bipolar disorder.[30][31][32] Nalbuphine (Nubain) and its prodrug dinalbuphine sebacate (Naldebain) are also dual KOR agonists and MOR agonists or antagonists used as analgesics.[33][34][35] Butorphanol (Stadol) is another opioid analgesic acting as a dual KOR agonist and MOR agonist or antagonist with analgesic and dysphoric effects.[36][37] Enadoline (CI-977) and spiradoline (U-62066) are highly selective KOR agonists that were under development as analgesics for treatment of pain but were abandoned due to side effects like hallucinogenic effects and dysphoria.[38]

Nalfurafine (Remitch) is an atypical centrally active but non-hallucinogenic KOR agonist with G protein bias which is approved for the treatment of pruritus (itching).[39][40] Difelikefalin (Korsuva) is a peripherally selective and hence likewise non-hallucinogenic KOR agonist which is approved and used in the treatment of pruritis as well.[8][9]

Noribogaine and ibogaine (via metabolism into noribogaine) act as potent atypical KOR agonists with G protein bias, among many other actions, and are found in Tabernanthe iboga (iboga).[41][42][43][44][45] Their KOR agonism may be involved in ibogaine's putative antiaddictive effects in the setting of opioid dependence.[44] Analogues with strongly enhanced KOR agonist potency such as oxa-noribogaine,[46] GM-3009,[47] and 4-allyl-6-oxa-noribogainalog have been developed.[48][49] GM-3009 is under development by Gilgamesh Pharmaceuticals for the treatment of opioid-related disorders.[50][51]

The selective KOR agonist and benzomorphan MR-2034 ((–)-MR-2033) led to the initial discovery in the 1980s that KOR agonists produce hallucinogenic and dysphoric effects as opposed to these effects being mediated by concomitant sigma receptor agonism.[52][53]

See also

References

  1. 1 2 3 4 5 Dalefield ML, Scouller B, Bibi R, Kivell BM (2022). "The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies". Front Pharmacol. 13 837671. doi:10.3389/fphar.2022.837671. PMC 9251383. PMID 35795569.
  2. ↑ Beck TC, Wilson EM, Wilkes E, Lee LW, Norris R, Valdebran M (2023). "Kappa opioid agonists in the treatment of itch: just scratching the surface?". Itch (Phila). 8 (4). doi:10.1097/itx.0000000000000072. PMC 10720604. PMID 38099236.
  3. 1 2 3 Hernández-Alvarado RB, Madariaga-Mazón A, Ortega A, Martinez-Mayorga K (December 2020). "DARK Classics in Chemical Neuroscience: Salvinorin A". ACS Chem Neurosci. 11 (23): 3979–3992. doi:10.1021/acschemneuro.0c00608. PMID 33164503.
  4. 1 2 Ji MJ, Yang J, Gao ZQ, Zhang L, Liu C (2021). "The Role of the Kappa Opioid System in Comorbid Pain and Psychiatric Disorders: Function and Implications". Front Neurosci. 15 642493. doi:10.3389/fnins.2021.642493. PMC 7943636. PMID 33716658.
  5. ↑ Lazenka MF (2022). "Antinociceptive Effects of Kappa-Opioid Receptor Agonists". The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 293–313. doi:10.1007/164_2020_430. ISBN 978-3-030-89073-5. PMID 33387069.
  6. ↑ Kaski SW, White AN, Gross JD, Siderovski DP (February 2021). "Potential for Kappa-Opioid Receptor Agonists to Engineer Nonaddictive Analgesics: A Narrative Review". Anesth Analg. 132 (2): 406–419. doi:10.1213/ANE.0000000000005309. PMC 7992303. PMID 33332902.
  7. ↑ Cowan A, Kehner GB, Inan S (2015). "Targeting Itch with Ligands Selective for κ Opioid Receptors". Pharmacology of Itch. Handbook of Experimental Pharmacology. Vol. 226. pp. 291–314. doi:10.1007/978-3-662-44605-8_16. ISBN 978-3-662-44604-1. PMID 25861786.
  8. 1 2 Fugal J, Serpa SM (April 2023). "Difelikefalin: A New κ-Opioid Receptor Agonist for the Treatment of Hemodialysis-Dependent Chronic Kidney Disease-Associated Pruritus". Ann Pharmacother. 57 (4): 480–488. doi:10.1177/10600280221115889. PMID 35942600.
  9. 1 2 Rastogi A, Fishbane S, Lerma E (May 2023). "Difelikefalin for the treatment of moderate-to-severe pruritus associated with chronic kidney disease on hemodialysis". Expert Rev Clin Pharmacol. 16 (5): 387–400. doi:10.1080/17512433.2023.2197209. PMID 37010031.
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