Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism Which Do Not Recruit
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Repository of the Academy's Library Subscriber access provided by University of Idaho Library Article Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism which do not recruit #-arrestin-2 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, and Susruta Majumdar J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.6b00748 • Publication Date (Web): 24 Aug 2016 Downloaded from http://pubs.acs.org on August 24, 2016 Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. 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Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts. Journal of Medicinal Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties. Page 1 of 64 Journal of Medicinal Chemistry 1 2 3 Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and 4 5 delta antagonism, which do not recruit β-arrestin-2 6 7 András Váradi a, Gina F. Marrone a, Travis C. Palmer a, Ankita Narayan a, Márton R. Szabó c, 8 Valerie Le Rouzic a, Steven G. Grinnell a, Joan J. Subrath a, Evelyn Warner a, Sanjay Kalra a, 9 a a b b a 10 Amanda Hunkele , Jeremy Pagirsky , Shainnel O. Eans , Jessica M. Medina , Jin Xu , Ying- 11 Xian Pan a, Attila Borics c, Gavril W Pasternak a, Jay P. McLaughlin b and Susruta Majumdar a,* 12 13 aMolecular Pharmacology & Chemistry Program and Department of Neurology, Memorial Sloan 14 15 Kettering Cancer Center, New York, NY 10065 16 bDepartment of Pharmacodyanamics, University of Florida, Gainesville, FL 032610 17 c 18 Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, 19 Szeged, Hungary H-6726 20 21 22 23 24 25 ABSTRACT 26 27 28 29 Natural products found in Mitragyna speciosa , commonly known as kratom , represent diverse 30 31 scaffolds (indole, indolenine and spiro pseudoindoxyl) with opioid activity, providing 32 33 opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and 34 35 36 SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl ( 3), an oxidative 37 38 rearrangement product of the corynanthe alkaloid mitragynine . 3 and its corresponding 39 40 corynantheidine analogs show promise as potent analgesics with a mechanism of action that 41 42 43 includes mu opioid receptor agonism-delta opioid receptor antagonism. In vitro, 3 and its analogs 44 45 were potent agonists in [ 35 S]GTPγS assays at the mu opioid receptor but failed to recruit β- 46 47 48 arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic 49 50 tolerance more slowly than morphine, showed limited physical dependence, respiratory 51 52 depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting 53 54 55 that analogs might represent a promising new generation of novel pain relievers. 56 57 58 59 60 ACS Paragon Plus Environment Journal of Medicinal Chemistry Page 2 of 64 1 2 3 INTRODUCTION 4 5 6 7 Opioids, including morphine, are clinically used for the treatment of moderate to severe 8 9 chronic pain. However, despite their proven efficacy, mu opioid receptor agonists have 10 11 1 12 problematic side effects such as tolerance, physical dependence, and substance abuse. Agonists 13 2-4 14 selective for other opioid receptors produce analgesia, but with their own liabilities. The 15 16 ultimate goal of opioid-related drug development has been to design and synthesize potent 17 18 19 antinociceptive agents that are devoid of adverse side effects. Many approaches have been taken 20 21 over the years, starting with the development of partial agonists or mixed agonist/antagonists. 5-9 22 23 A more recent approach takes advantage of biased agonism, in which distinct downstream 24 25 10, 11 26 signaling pathways are activated by different agonists working through the same receptor. It 27 28 has been proposed that ligands biased against recruiting β-arrestin-2, or showing preference for 29 30 activating specific G-protein mediated signal transduction pathways, will demonstrate 31 32 12, 13 14, 15 33 diminished side effects. Oliceridine (TRV130) is an example of a mu-opioid receptor 34 35 biased agonist which has recently entered phase-III clinical trials, showing separation between 36 37 16 38 antinociception and some opioid-related side effects. 6'-Guanidinonaltrindole (6’-GNTI), 22- 39 17 40 thiocyanatosalvinorin A (RB-64), and two new classes of kappa opioid ligands from the Aube 41 42 group have also recently been reported in the opioid literature as biased kappa opioid receptor 43 44 18, 19 45 agonists. 46 47 Natural products have provided many lead compounds leading to the design of new 48 49 pharmaceuticals. Natural products and their derivatives account for approximately 50% of 50 51 20 52 approved drugs. Morphine, the most commonly employed opioid, and thebaine, the structure 53 54 on which the vast majority of semi-synthetic opiates is based, are natural alkaloids found in the 55 56 poppy plant, Papaver somniferum . While opioid chemistry has traditionally been dominated by 57 58 59 60 ACS Paragon Plus Environment Page 3 of 64 Journal of Medicinal Chemistry 1 2 3 thebaine-derived alkaloids isolated from poppy, there are a growing number of opioid natural 4 5 6 products derived from structures other than the traditional morphinan scaffold and thus 7 8 structurally not closely related to morphine. These include analogs of salvinorin A 21-23 such as 9 10 24 17 11 herkinorin and thiocyanatosalvinorin A , which have been developed as mu- and kappa-opioid 12 13 receptor biased agonists, respectively, while some peptide analogs such as cyclo[Phe-d-Pro-Phe- 14 15 Trp] (CJ-15,208) 25 are being developed as analgesics and medications against cocaine abuse 16 17 18 (Figure 1). Mitragynine (indole core) (1) and its congeners isolated from the Southeast Asian 19 20 plant Mitragyna speciosa , commonly known as kratom , are monoterpene indole alkaloids 21 22 structurally not closely related to morphine. 26 In addition to its traditional use, kratom has 23 24 25 become a quickly emerging substance of abuse. It is currently legal in many parts of the world, 26 27 and kratom leaves are available for purchase over the internet. Case studies of fatalities resulting 28 29 from overdose have been published, although the risk posed by mitragynine remains uncertain, 30 31 32 given that simultaneous use or contamination with other substances (including opioids) that may 33 34 have been involved in the reported deaths.27-30 Both mitragynine ( 1) and its naturally occurring 35 36 37 oxidation product, 7-OH mitragynine (indolenine core) (2), are opioid antinociceptive agents that 38 31-39 39 have been examined both in vitro and in vivo . Mitragynine pseudoindoxyl (3), a 40 41 rearrangement product of 2 with a spiro-pseudoindoxyl core, was first isolated in 1974 by 42 43 40 44 Zarembo et al. as a microbial metabolite of 1 by the fungus Helminthosporum sp . Yamamoto et 45 46 al. reported that it acted non-selectively on mu- and delta-opioid receptors while its kappa-opioid 47 48 receptor affinity was negligible. 41 In later publications by Takayama et al., the in vivo 49 50 39 51 supraspinal analgesic properties of 3 were briefly discussed. 52 53 54 In this work, we report the in vitro and in vivo pharmacology and structure-activity 55 56 relationships (SAR) of mitragynine pseudoindoxyl (3). We demonstrate for the first time that 3 57 58 59 60 ACS Paragon Plus Environment Journal of Medicinal Chemistry Page 4 of 64 1 2 3 and its C-9 substituted derivatives, corynantheidine pseudoindoxyls, are systemically active 4 5 6 mixed mu-opioid receptor agonist/delta-opioid receptor antagonist compounds in vitro, and 7 8 produce potent antinociception in vivo . Characterization of 3 demonstrated opioid-mediated 9 10 11 analgesia devoid of any place-conditioning effects, and a side effect profile far superior to 12 13 clinically used mu opioid based antinociceptive agents. 14 15 16 RESULTS 17 18 19 20 Chemistry: 21 22 1 was extracted from dry kratom powder using a modified protocol reported by Ponglux 23 24 et al.