Abstract Title:

Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism which do not recruitβ-arrestin-2.

Abstract Source:

J Med Chem. 2016 Aug 24. Epub 2016 Aug 24. PMID: 27556704

Abstract Author(s):

András Váradi, Gina F Marrone, Travis C Palmer, Ankita Narayan, Márton R Szabó, Valerie Le Rouzic, Steven G Grinnell, Joan J Subrath, Evelyn Warner, Sanjay Kalra, Amanda Hunkele, Jeremy Pagirsky, Shainnel O Eans, Jessica M Medina, Jin Xu, Ying Xian Pan, Attila Borics, Gavril W Pasternak, Jay P McLaughlin, Susruta Majumdar

Article Affiliation:

András Váradi

Abstract:

Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism-delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [(35)S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.

Study Type : Animal Study, In Vitro Study
Additional Links
Pharmacological Actions : Analgesics : CK(2569) : AC(470)

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