Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit beta-Arrestin-2.

Varadi, A; Marrone, GF; Palmer, TC; Narayan, A; Szabo, MR [Szabó, Márton Richárd (biokémia), szerző] Biokémiai Intézet (SZBK); Le Rouzic, V; Grinnell, SG; Subrath, JJ; Warner, E; Kalra, S; Hunkele, A; Pagirsky, J; Eans, SO; Medina, JM; Xu, J; Pan, YX; Borics, A [Borics, Attila (Peptid- és fehérj...), szerző] Biokémiai Intézet (SZBK); Pasternak, GW; McLaughlin, JP; Majumdar, S

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: JOURNAL OF MEDICINAL CHEMISTRY 0022-2623 1520-4804 59 (18) pp. 8381-8397 2016
  • SJR Scopus - Drug Discovery: D1
    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 [35S]GTPgammaS assays at the mu opioid receptor but failed to recruit beta-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.
    Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSLMásolásNyomtatás
    2022-01-23 21:46