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).
Biosynthesis
This molecule is biosynthetically related to the morphinane derivatives metabolism, where thebaine and morphine are implicated.[11]
Morphine biosynthesis
References
^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. PMID6121539.
^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. PMID14334338. S2CID4296776.
^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. PMID6042763.
^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. PMID6042765.
^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. PMID6042764.
^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.
