title: Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2.
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.
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: András
authors.initials: A
authors.lastname: Váradi
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Gina F
authors.initials: GF
authors.lastname: Marrone
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Travis C
authors.initials: TC
authors.lastname: Palmer
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Ankita
authors.initials: A
authors.lastname: Narayan
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Szeged, H-6726 Hungary.
authors.forename: Márton R
authors.initials: MR
authors.lastname: Szabó
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Valerie
authors.initials: V
authors.lastname: Le Rouzic
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Grinnell
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Subrath
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Warner
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kalra
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: Hunkele
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Pagirsky
authors.affiliation: Department of Pharmacodyanamics, University of Florida , Gainesville, Florida 032610, United States.
authors.forename: Shainnel O
authors.initials: SO
authors.lastname: Eans
authors.affiliation: Department of Pharmacodyanamics, University of Florida , Gainesville, Florida 032610, United States.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Medina
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Ying-Xian
authors.initials: YX
authors.lastname: Pan
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Szeged, H-6726 Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Borics
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
authors.affiliation: Department of Pharmacodyanamics, University of Florida , Gainesville, Florida 032610, United States.
authors.forename: Jay P
authors.initials: JP
authors.lastname: McLaughlin
authors.affiliation: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Susruta
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D006801:Humans; D008297:Male; D051379:Mice; D032065:Mitragyna / Q000737:chemistry; D062105:Molecular Docking Simulation; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D046948:Secologanin Tryptamine Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000071560:beta-Arrestin 2 / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D046948:Secologanin Tryptamine Alkaloids; D000071560:beta-Arrestin 2; C121049:mitragynine pseudoindoxyl