Oripavine is an opioid and the major metabolite of thebaine. It is the parent compound from which a series of semi-synthetic opioids are derived, which includes the compounds etorphine and buprenorphine. Although its analgesic potency is comparable to morphine, it is not used clinically due to its severe toxicity and low therapeutic index. Due to its use in manufacture of strong opioids, oripavine is a controlled substance in some jurisdictions.
Of much greater relevance are the properties of the orvinols, a large family of semi-synthetic oripavine derivatives classically synthesized by the Diels-Alder reaction of thebaine with an appropriate dienophile followed by 3-O-demethylation to the corresponding bridged oripavine. These compounds were developed by the group led by K. W. Bentley in the 1960s, and these Bentley compounds represent the first series of "super-potent" μ-opioid agonists, with some compounds in the series being over 10,000 times the potency of morphine as an analgesic.[3][4][5] The simple bridged oripavine parent compound 6,14-endoethenotetrahydrooripavine is already 40 times the potency of morphine,[6] but adding a branched tertiary alcohol substituent on the C7 position results in a wide range of highly potent compounds.[7]
Other notable derivatives then result from further modification of this template, with saturation of the 7,8-double bond of etorphine resulting in the even more potent dihydroetorphine (up to 12,000× potency of morphine) and acetylation of the 3-hydroxy group of etorphine resulting in acetorphine (8700× morphine)—although while the isopentyl homologue of etorphine is nearly three times more potent, its 7,8-dihydro and 3-acetyl derivatives are less potent than the corresponding derivatives of etorphine at 11,000 and 1300 times morphine, respectively. Replacing the N-methyl group with cyclopropylmethyl results in opioid antagonists such as diprenorphine (M5050, which is used as an antidote to reverse the effects of etorphine, M99), and partial agonists such as buprenorphine, which is widely used in the treatment of opioid addiction.
Under the Controlled Substances Act 1970, oripavine has an ACSCN of 9330 and a 2013 manufacturing quota of 22,750 kg (50,160 lb).
BiosynthesisEdit
This molecule is biosynthetically related to the morphinane derivatives metabolism, where thebaine and morphine are implicated.[11]
Morphine biosynthesis
ReferencesEdit
^Yeh, SY (December 1981). "Analgesic activity and toxicity of oripavine and phi-dihydrothebaine in the mouse and rat". Archives Internationales de Pharmacodynamie et de Thérapie. 254 (2): 223–40. PMID 6121539.
^Chanoit, Pierre; et al. (1981). "Dependence potential of oripavine". Bulletin on Narcotics. 33 (3): 29–35. PMID 7039748. Retrieved 2007-10-05.
^Bentley, K. W.; Boura, A. L.; Fitzgerald, A. E.; Hardy, D. G.; McCoubrey, A; Aikman, M. L.; Lister, R. E. (1965). "Compounds Possessing Morphine-Antagonizing or Powerful Analgesic Properties". Nature. 206 (4979): 102–3. Bibcode:1965Natur.206..102B. doi:10.1038/206102a0. PMID 14334338. S2CID 4296776.
^Bentley, K. W.; Hardy, D. G.; Meek, B (1967). "Novel analgesics and molecular rearrangements in the morphine-thebaine group. II. Alcohols derived from 6,14-endo-etheno- and 6,14-endo-ethanotetrahydrothebaine". Journal of the American Chemical Society. 89 (13): 3273–80. doi:10.1021/ja00989a031. PMID 6042763.
^Bentley, K. W.; Hardy, D. G.; Meek, B (1967). "Novel analgesics and molecular rearrangements in the morphine-thebaine group. IV. Acid-catalyzed rearrangements of alcohols of the 6,14-endo-ethenotetrahydrothebaine series". Journal of the American Chemical Society. 89 (13): 3293–303. doi:10.1021/ja00989a033. PMID 6042765.
^Lewis, J. W.; Bentley, K. W.; Cowan, A (1971). "Narcotic analgesics and antagonists". Annual Review of Pharmacology. 11: 241–70. doi:10.1146/annurev.pa.11.040171.001325. PMID 4948499.
^Bentley, K. W.; Hardy, D. G. (1967). "Novel analgesics and molecular rearrangements in the morphine-thebaine group. 3. Alcohols of the 6,14-endo-ethenotetrahydrooripavine series and derived analogs of N-allylnormorphine and -norcodeine". Journal of the American Chemical Society. 89 (13): 3281–92. doi:10.1021/ja00989a032. PMID 6042764.
^WHO Expert Committee on Drug Dependence. "Thirty-third report". WHO Technical Report Series, No. 915. Geneva, World Health Organization, 2003. Accessed September 17, 2007.
^UN Commission on Narcotic Drugs. "Decision 50/1: Inclusion of oripavine in Schedule I of the Single Convention on Narcotic Drugs of 1961 and that Convention as amended by the 1972 Protocol." Report on the fiftieth session. Document E/CN.7/2007/16, p 52. Geneva, United Nations Office on Drugs and Crime, 2007. Accessed September 18, 2007.
^Drug Enforcement Administration. "Designation of Oripavine as a Basic Class of Controlled Substance." Federal Register. September 2007; 72 (184):p54208-54210. Accessed October 25, 2007.
^Novak; et al. (2000). "Morphine Synthesis and Biosynthesis—An Update" (PDF). Current Organic Chemistry. 4 (3): 343–362. CiteSeerX10.1.1.515.9096. doi:10.2174/1385272003376292.
October 16, 2023
oripavine, opioid, major, metabolite, thebaine, parent, compound, from, which, series, semi, synthetic, opioids, derived, which, includes, compounds, etorphine, buprenorphine, although, analgesic, potency, comparable, morphine, used, clinically, severe, toxici. Oripavine is an opioid and the major metabolite of thebaine It is the parent compound from which a series of semi synthetic opioids are derived which includes the compounds etorphine and buprenorphine Although its analgesic potency is comparable to morphine it is not used clinically due to its severe toxicity and low therapeutic index Due to its use in manufacture of strong opioids oripavine is a controlled substance in some jurisdictions Oripavine NamesIUPAC name 6 7 8 14 Tetradehydro 4 5a epoxy 6 methoxy 17 methylmorphinan 3 olOther names 3 O desmethylthebaineIdentifiersCAS Number 467 04 9 N3D model JSmol Interactive imageChEBI CHEBI 7782 YChEMBL ChEMBL437602 YChemSpider 4575366 YECHA InfoCard 100 006 715EC Number 207 385 6KEGG C06175 NMeSH OripavinePubChem CID 5462306UNII 575AOU51CR NCompTox Dashboard EPA DTXSID10196908InChI InChI 1S C18H19NO3 c1 19 8 7 18 11 4 6 14 21 2 17 18 22 16 13 20 5 3 10 15 16 18 9 12 11 19 h3 6 12 17 20H 7 9H2 1 2H3 t12 17 18 m1 s1 YKey ZKLXUUYLEHCAMF UUWFMWQGSA N YInChI 1S C18H19NO3 c1 19 8 7 18 11 4 6 14 21 2 17 18 22 16 13 20 5 3 10 15 16 18 9 12 11 19 h3 6 12 17 20H 7 9H2 1 2H3 t12 17 18 m1 s1Key ZKLXUUYLEHCAMF UUWFMWQGBLKey ZKLXUUYLEHCAMF UUWFMWQGSA NSMILES OC1 C O C H 2C OC CC C3 C 42CCN5C C4 C C C H 35 C C1PropertiesChemical formula C 18H 19N O 3Molar mass 297 348 g molPharmacologyATC code N02A WHO Routes ofadministration SCLegal status BR Class A1 Narcotic drugs US Schedule IIExcept where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa N verify what is Y N Infobox references Contents 1 Pharmacological properties 1 1 Bridged derivatives 2 Legal status 3 Biosynthesis 4 ReferencesPharmacological properties EditOripavine possesses an analgesic potency comparable to morphine however it is not clinically useful due to severe toxicity and low therapeutic index In both mice and rats toxic doses caused tonic clonic seizures followed by death similar to thebaine 1 Oripavine has a potential for dependence which is significantly greater than that of thebaine but slightly less than that of morphine 2 Bridged derivatives Edit Of much greater relevance are the properties of the orvinols a large family of semi synthetic oripavine derivatives classically synthesized by the Diels Alder reaction of thebaine with an appropriate dienophile followed by 3 O demethylation to the corresponding bridged oripavine These compounds were developed by the group led by K W Bentley in the 1960s and these Bentley compounds represent the first series of super potent m opioid agonists with some compounds in the series being over 10 000 times the potency of morphine as an analgesic 3 4 5 The simple bridged oripavine parent compound 6 14 endoethenotetrahydrooripavine is already 40 times the potency of morphine 6 but adding a branched tertiary alcohol substituent on the C7 position results in a wide range of highly potent compounds 7 nbsp Drug name R Analgesic Potency Morphine 1 isobutyl 10phenyl 34n hexyl 58methyl 63cyclopentyl 70ethyl 330phenethyl 2200Etorphine n propyl 3200cyclohexyl 3400n pentyl 4500n butyl 5200M320 opioid isopentyl 9200Other notable derivatives then result from further modification of this template with saturation of the 7 8 double bond of etorphine resulting in the even more potent dihydroetorphine up to 12 000 potency of morphine and acetylation of the 3 hydroxy group of etorphine resulting in acetorphine 8700 morphine although while the isopentyl homologue of etorphine is nearly three times more potent its 7 8 dihydro and 3 acetyl derivatives are less potent than the corresponding derivatives of etorphine at 11 000 and 1300 times morphine respectively Replacing the N methyl group with cyclopropylmethyl results in opioid antagonists such as diprenorphine M5050 which is used as an antidote to reverse the effects of etorphine M99 and partial agonists such as buprenorphine which is widely used in the treatment of opioid addiction Legal status EditDue to the relative ease of synthetic modification of oripavine to produce other narcotics by either direct or indirect routes via thebaine the World Health Organization s Expert Committee on Drug Dependence recommended in 2003 that oripavine be controlled under Schedule I of the 1961 Single Convention on Narcotic Drugs 8 On March 14 2007 the United Nations Commission on Narcotic Drugs formally decided to accept these recommendations and placed oripavine in the Schedule I 9 Until recently oripavine was a Schedule II drug in the United States by default as a thebaine derivative although it was not explicitly listed However as a member state under the 1961 Single Convention on Narcotic Drugs the US was obliged to specifically control the substance under the Controlled Substances Act following its international control by the UN Commission on Narcotic Drugs On September 24 2007 the Drug Enforcement Administration formally added oripavine to Schedule II 10 Under the Controlled Substances Act 1970 oripavine has an ACSCN of 9330 and a 2013 manufacturing quota of 22 750 kg 50 160 lb Biosynthesis EditThis molecule is biosynthetically related to the morphinane derivatives metabolism where thebaine and morphine are implicated 11 nbsp Morphine biosynthesisReferences Edit Yeh SY December 1981 Analgesic activity and toxicity of oripavine and phi dihydrothebaine in the mouse and rat Archives Internationales de Pharmacodynamie et de Therapie 254 2 223 40 PMID 6121539 Chanoit Pierre et al 1981 Dependence potential of oripavine Bulletin on Narcotics 33 3 29 35 PMID 7039748 Retrieved 2007 10 05 Bentley K W Boura A L Fitzgerald A E Hardy D G McCoubrey A Aikman M L Lister R E 1965 Compounds Possessing Morphine Antagonizing or Powerful Analgesic Properties Nature 206 4979 102 3 Bibcode 1965Natur 206 102B doi 10 1038 206102a0 PMID 14334338 S2CID 4296776 Bentley K W Hardy D G Meek B 1967 Novel analgesics and molecular rearrangements in the morphine thebaine group II Alcohols derived from 6 14 endo etheno and 6 14 endo ethanotetrahydrothebaine Journal of the American Chemical Society 89 13 3273 80 doi 10 1021 ja00989a031 PMID 6042763 Bentley K W Hardy D G Meek B 1967 Novel analgesics and molecular rearrangements in the morphine thebaine group IV Acid catalyzed rearrangements of alcohols of the 6 14 endo ethenotetrahydrothebaine series Journal of the American Chemical Society 89 13 3293 303 doi 10 1021 ja00989a033 PMID 6042765 Lewis J W Bentley K W Cowan A 1971 Narcotic analgesics and antagonists Annual Review of Pharmacology 11 241 70 doi 10 1146 annurev pa 11 040171 001325 PMID 4948499 Bentley K W Hardy D G 1967 Novel analgesics and molecular rearrangements in the morphine thebaine group 3 Alcohols of the 6 14 endo ethenotetrahydrooripavine series and derived analogs of N allylnormorphine and norcodeine Journal of the American Chemical Society 89 13 3281 92 doi 10 1021 ja00989a032 PMID 6042764 WHO Expert Committee on Drug Dependence Thirty third report WHO Technical Report Series No 915 Geneva World Health Organization 2003 Accessed September 17 2007 UN Commission on Narcotic Drugs Decision 50 1 Inclusion of oripavine in Schedule I of the Single Convention on Narcotic Drugs of 1961 and that Convention as amended by the 1972 Protocol Report on the fiftieth session Document E CN 7 2007 16 p 52 Geneva United Nations Office on Drugs and Crime 2007 Accessed September 18 2007 Drug Enforcement Administration Designation of Oripavine as a Basic Class of Controlled Substance Federal Register September 2007 72 184 p54208 54210 Accessed October 25 2007 Novak et al 2000 Morphine Synthesis and Biosynthesis An Update PDF Current Organic Chemistry 4 3 343 362 CiteSeerX 10 1 1 515 9096 doi 10 2174 1385272003376292 Retrieved from https en wikipedia org w index php title Oripavine amp oldid 1177323436, wikipedia, wiki, book, books, library,
