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

A. 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

Research output: Contribution to journalArticle

71 Citations (Scopus)

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 [35S]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.

Original languageEnglish
Pages (from-to)8381-8397
Number of pages17
JournalJournal of Medicinal Chemistry
Volume59
Issue number18
DOIs
Publication statusPublished - Sep 22 2016

Fingerprint

Opioid Analgesics
mu Opioid Receptor
Analgesics
Mitragyna
Pharmacology
delta Opioid Receptor
Constipation
Biological Products
Reward
Alkaloids
Respiratory Insufficiency
Morphine
Pain
beta-Arrestin 1
mitragynine pseudoindoxyl
In Vitro Techniques
3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid
mitragynine
corynanthe
indole

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2. / Váradi, A.; Marrone, Gina F.; Palmer, Travis C.; Narayan, Ankita; Szabó, Márton R.; Le Rouzic, Valerie; Grinnell, Steven G.; Subrath, Joan J.; Warner, Evelyn; Kalra, Sanjay; Hunkele, Amanda; Pagirsky, Jeremy; Eans, Shainnel O.; Medina, Jessica M.; Xu, Jin; Pan, Ying Xian; Borics, Attila; Pasternak, Gavril W.; McLaughlin, Jay P.; Majumdar, Susruta.

In: Journal of Medicinal Chemistry, Vol. 59, No. 18, 22.09.2016, p. 8381-8397.

Research output: Contribution to journalArticle

Váradi, A, Marrone, GF, Palmer, TC, Narayan, A, Szabó, MR, 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, Pasternak, GW, McLaughlin, JP & Majumdar, S 2016, 'Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2', Journal of Medicinal Chemistry, vol. 59, no. 18, pp. 8381-8397. https://doi.org/10.1021/acs.jmedchem.6b00748
Váradi, A. ; Marrone, Gina F. ; Palmer, Travis C. ; Narayan, Ankita ; Szabó, Márton R. ; Le Rouzic, Valerie ; Grinnell, Steven G. ; Subrath, Joan J. ; Warner, Evelyn ; Kalra, Sanjay ; Hunkele, Amanda ; Pagirsky, Jeremy ; Eans, Shainnel O. ; Medina, Jessica M. ; Xu, Jin ; Pan, Ying Xian ; Borics, Attila ; Pasternak, Gavril W. ; McLaughlin, Jay P. ; Majumdar, Susruta. / Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 18. pp. 8381-8397.
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