Classics in Chemical Neuroscience: Buprenorphine Jillian L Kyzer, and Cody J Wenthur ACS Chem
Total Page：16
File Type：pdf, Size：1020Kb
Subscriber access provided by INFOTRIEVE INC Review Classics In Chemical Neuroscience: Buprenorphine Jillian L Kyzer, and Cody J Wenthur ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.0c00100 • Publication Date (Web): 17 Apr 2020 Downloaded from pubs.acs.org on April 24, 2020 Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. 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. 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 19 ACS Chemical Neuroscience 1 2 3 4 5 6 7 CLASSICS IN CHEMICAL NEUROSCIENCE: 8 BUPRENORPHINE 9 10 Jillian L. Kyzer, Cody J. Wenthur 11 12 University of Wisconsin-Madison, School of Pharmacy, 777 Highland Avenue, Madison, WI 53705, United States 13 ABSTRACT: Buprenorphine has not only had an interdisciplinary impact on our understanding of key neuroscience topics like 14 opioid pharmacology, pain signaling, and reward processing, but has also been a key influence in changing the way that substance 15 use disorders are approached in modern medical systems. From its leading role in expanding outpatient treatment of opioid use 16 disorders to its continued influence on research into next-generation analgesics, buprenorphine has been a continuous player in the 17 ever-evolving societal perception of opioids and substance use disorder. To provide a multifaceted account on the enormous diversity 18 of areas where this molecule has made an impact, this article discusses buprenorphine’s chemical properties, synthesis and 19 development, pharmacology, adverse effects, manufacturing information, and historical place in the field of chemical neuroscience. 20 KEY WORDS: buprenorphine, opioid use disorder, Suboxone, MAT, OUD 21 22 23 24 INTRODUCTION 25 While all neuropsychiatric disorders present daunting 26 biological challenges arising from the sheer complexity of the 27 central nervous system, research on substance use disorder 28 (SUD) has historically found itself fraught by equally 29 challenging complexities arising from a completely different 30 type of system – a sociopolitical one. Throughout history, 31 opioids have been paraded through the intersection where 32 biology and politics meet, sometimes hated, sometimes heralded. Viewed over time, one can almost see rhetorical ruts 33 being worn into the pavement there, as the same arguments are 34 repeatedly marshalled to take up their side of the cause. But in 35 recent decades, one opioid molecule has found itself somewhat 36 ill-suited to stay within the confines of these pre-defined paths, 37 making an impressive wake in its passage. That molecule is 38 buprenorphine, a mu opioid receptor (μOP) partial agonist. Buprenorphine’s unique mechanism of action, especially its 39 Buprenorphine has 7 stereocenters, carries the molecular lower risk for inducing respiratory depression as compared to 40 formula of C H NO , and has a molecular weight of 467.65 other opioids, has enabled it to form the foundation of the 29 41 4 41 g/mol. The free-base has a melting point of 209 ºC, though it is office-based opioid treatment (OBOT) approach for opioid use 42 commonly manufactured as the hydrochloride salt.1 With 2 disorder (OUD), a therapeutic intervention that was once a legal 43 hydrogen bond donors, 5 hydrogen bond acceptors, 5 rotatable anathema in the United States. Furthermore, investigations bonds, a topological polar surface area of 62.16 Å2, and ClogP 44 stemming from the specific pharmacological profile of of 3.809, buprenorphine meets all of Lipinski’s rules of five.2–4 45 buprenorphine have been instrumental in opening the door to Buprenorphine (1, Chart 1) is a semisynthetic derivative of 46 investigations of next-generation opioid therapeutics. As one of the natural product thebaine (2), which is isolated from the 47 the primary treatments for OUD, this compound has already 48 made an enormous, life-saving impact on millions of opium poppy, with a concentration of 41 g/g detectable in the Indian poppy seed.5 In support of production, cultivars of the 49 individuals. However, without careful study of the anomalous pharmacologic properties of this otherwise modestly successful poppy have been bred to produce a larger percentage of 50 thebaine (1.68% by mass of dried poppy capsules) and with no 51 opioid analgesic medication, buprenorphine’s potential to 6 advance both basic neuroscience and clinical psychiatry might morphine (3). In a separate effort, Millgate and coworkers 52 created a mutant poppy strain that arrests the biosynthesis 53 easily have been missed. pathway at thebaine and oripavine (4), preventing conversion 54 7 CHEMICAL PROPERTIES AND SYNTHESIS to codeine (5) or morphine. Structurally, buprenorphine is 55 The drug commonly known as buprenorphine carries the quite different from thebaine, containing a N- 56 IUPAC name N-cyclopropylmethyl-6,14-endo-ethano-7-(2- cyclopropylmethyl (CPM) instead of an N-methyl, an 57 hydroxy-3,3-dimethyl-2-butyl)-tetrahydronororipavine. additional ring, and a hydroxybutane tail. At present, each of 58 59 1 60 ACS Paragon Plus Environment ACS Chemical Neuroscience Page 2 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 these distinguishing features are installed using classical acetyl group provided 6,14-endo-ethano-7-(2-hydroxy-3,3- 47 organic synthesis approaches. dimethyl-2-butyl)-tetrahydrothebaine (8).1 N-demethylation 48 In initial work by Bentley and coworkers, the synthetic occurred via reaction with cyanogen bromide to yield the N- 49 portion of the semi-synthesis began with thebaine’s diene cyano-desmethyl intermediate 9, and basic hydrolysis was moiety, which readily reacted with methyl vinyl ketone in a utilized to provide the secondary amine 6,14-endo-ethano-7-(2- 50 Diels-Alder cycloaddition to provide the endo product, with no hydroxy-3,3-dimethyl-2-butyl)-tetrahydronorthebaine (10).1 51 evidence of addition at C8 (Scheme 1).8,9 Following Acylation of the amine with cyclopropyl carbonyl chloride 52 recrystallization, it was determined that the 7 product was provided the amide 11, which was subsequently reduced with 53 obtained as the major product, 6,14-endo-etheno-7-acetyl- lithium aluminum hydride to yield N-cyclopropylmethyl-6,14- 54 tetrahydrothebaine (6), while the mother liquor contained endo-ethano-7-(2-hydroxy-3,3-dimethyl-2-butyl)- 55 approximately 1.5% of the 7 product.9 Following the tetrahydronorthebaine (12).1 Finally, O-demethylation with 56 reduction of the internal double bond via Pd/C hydrogenation potassium hydroxide in ethylene glycol resulted in the desired 57 to 6,14-endo-ethano-7-acetyl-tetrahydrothebaine (7), a product, N-cyclopropylmethyl-6,14-endo-ethano-7-(2- 58 Grignard addition of tert-butyl magnesium chloride into the 7- 59 2 60 ACS Paragon Plus Environment Page 3 of 19 ACS Chemical Neuroscience hydroxy-3,3-dimethyl-2-butyl)-tetrahydronororipavine (1), further potentiated by pertussis toxin (PTX) treatment after 18 1 with an overall yield of 5%.1 hours.25 This element of its profile has also been a source of 2 Alternative routes developed since this initial attempt have significant interest, as opioid-induced receptor internalization 3 shortened the synthesis from eight total steps to six (Scheme 2). has been proposed as an important mediator of tolerance.26 4 Hudlicky’s approach also has the benefit of avoiding the use of Amongst these various in vitro effects of buprenorphine on 5 the toxic reagent cyanogen bromide through use of a palladium- opioid signaling, rodent studies have predominantly identified 6 catalyzed acylation with cyclopropanecarboxylic anhydride or μOP activity as the key mediator of buprenorphine’s acetic anhydride, which also removes the N-methyl group.10,11 antinociceptive and reward effects in vivo. In μOP knockout 7 Hudlicky’s group also demonstrated that it was possible to mice buprenorphine-mediated antinociception is blunted, while 8 utilize oripavine (4) as the starting material, protecting the δOP, κOP, and NOP knockouts produce no differentiation