Of much greater relevance are the properties of the orvinols, a large family of semi-synthetic oripavine derivatives classically synthesized by theDiels-Alder reaction ofthebaine with an appropriate dienophile followed by 3-O-demethylation to the corresponding bridged oripavine. These compounds were developed by the group led byK. W. Bentley in the 1960s, and theseBentley 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 compound6,14-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 potentdihydroetorphine (up to 12,000× potency of morphine) and acetylation of the 3-hydroxy group of etorphine resulting inacetorphine (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 theN-methyl group with cyclopropylmethyl results inopioid antagonists such asdiprenorphine (M5050, which is used as an antidote to reverse the effects of etorphine, M99), andpartial agonists such asbuprenorphine, which is widely used in the treatment ofopioid addiction.
^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.Bibcode:1967JAChS..89.3273B.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.Bibcode:1967JAChS..89.3293B.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.Bibcode:1967JAChS..89.3281B.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 sessionArchived 2007-06-10 at theWayback Machine. Document E/CN.7/2007/16, p 52. Geneva, United Nations Office on Drugs and Crime, 2007. Accessed September 18, 2007.
