Hubbry Logo
OripavineOripavineMain
Open search
Oripavine
Community hub
Oripavine
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Contribute something
Oripavine
Oripavine
Oripavine
View on Wikipedia
from Wikipedia
Oripavine
Names
IUPAC name
6,7,8,14-Tetradehydro-4,5α-epoxy-6-methoxy-17-methylmorphinan-3-ol
Other names
3-O-desmethylthebaine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.006.715 Edit this at Wikidata
EC Number
  • 207-385-6
KEGG
MeSH Oripavine
UNII
  • 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 checkY
    Key: ZKLXUUYLEHCAMF-UUWFMWQGSA-N checkY
  • 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
    Key: ZKLXUUYLEHCAMF-UUWFMWQGBL
  • Key: ZKLXUUYLEHCAMF-UUWFMWQGSA-N
  • OC1=C(O[C@H]2C(OC)=CC=C3[C@@]42CCN5C)C4=C(C[C@H]35)C=C1
Properties
C18H19NO3
Molar mass 297.348 g/mol
Pharmacology
N02A (WHO)
SC
Legal status
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Oripavine is an opioid and the major metabolite of thebaine. It is the precursor to the semi-synthetic compounds etorphine and buprenorphine. Although this chemical compound has analgesic potency comparable to morphine, it is not used clinically due to severe adverse effects and a low therapeutic index. Being a precursor to a series of extremely strong opioids, oripavine is a controlled substance in some jurisdictions.

Pharmacological properties

[edit]

Oripavine 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 (The Bentley compounds)

[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" 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]

Drug name R Analgesic Potency (Morphine = 1)
isobutyl 10
phenyl 34
n-hexyl 58
methyl 63
cyclopentyl 70
ethyl 330
phenethyl 2200
Etorphine n-propyl 3200
cyclohexyl 3400
n-pentyl 4500
n-butyl 5200
M320 (opioid) isopentyl 9200

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.

[edit]

Due 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

[edit]

This molecule is biosynthetically related to the morphinane derivatives metabolism, where thebaine and morphine are implicated.[11]

Morphine biosynthesis
Morphine biosynthesis

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Oripavine

View on Grokipedia
from Grokipedia

Oripavine is a naturally occurring phenanthrene opioid alkaloid with the molecular formula C₁₈H₁₉NO₃, found in species of the Papaver genus including Papaver orientale and Papaver bracteatum. It functions as the primary metabolite of thebaine, formed through O-demethylation, and represents a key branch point in the biosynthetic pathway of morphine alkaloids in opium-producing plants. Oripavine possesses effects comparable to but demonstrates greater , with lower LD₅₀ values reported in animal studies relative to . As a phenolic derivative featuring a conjugated 6,8-diene in its core, it serves as a critical precursor for the semi-synthesis of potent derivatives, including —a partial μ- receptor used for pain relief and maintenance —and etorphine, an ultra-potent full employed in veterinary immobilization of large animals. Due to its role in pharmaceutical production of controlled substances, oripavine has been classified as a List I chemical under U.S. regulations since , subjecting it to strict monitoring to prevent diversion.

Chemical Properties

Molecular Structure and Formula

Oripavine has the molecular formula C₁₈H₁₉NO₃ and a of 297.35 g/mol. This formula reflects its composition as a morphinane , consisting of 18 carbon atoms, 19 atoms, one atom, and three oxygen atoms. Structurally, oripavine is the 3-O-demethylated derivative of thebaine, featuring a characteristic morphinan skeleton with a phenanthrene core fused to a piperidine ring and an additional dihydrofuran bridge between carbons 4 and 5. It includes a phenolic hydroxyl group at position 3, a methoxy group at position 6, a Δ7,8 double bond, and a conjugated diene system in ring C (Δ8,14), along with a N-methyl group. The stereochemistry is defined by specific chiral centers, typically (5α,6α,14α), contributing to its rigid tetracyclic framework. The IUPAC name for oripavine is (4R,7S,7aR,12bS)-7-methoxy-3-methyl-2,4,5,6,7,7a,12b-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-6,10-diol, though it is often described in relative to derivatives. This structure enables its role as a key intermediate in the synthesis of semisynthetic s, distinguishing it from fully methylated analogs like (C₁₉H₂₁NO₃).

Physical and Spectroscopic Characteristics

Oripavine appears as . It has a of 200–201 °C. The specific optical rotation is [α]D20 = −211.8° (concentration and solvent unspecified in available data). The molecular formula is C18H19NO3, with a molecular weight of 297.35 g/mol. Experimental solubility data for the are limited; like related alkaloids, it exhibits low water but forms soluble salts such as the . Predicted boiling point is approximately 480 °C at standard pressure. Ultraviolet spectroscopy reveals characteristic absorption maxima (λmax) at 207 nm (log ε = 4.45), 228 nm (log ε = 4.07), and 286 nm (log ε = 3.84) in ethanol, consistent with the phenolic and aromatic chromophores in its morphinan structure. Infrared spectroscopy shows key absorption bands indicative of phenolic OH (around 3300 cm−1), aromatic C=C (1605 cm−1), and ether functionalities, though detailed full spectra are not widely reported for the parent compound. Nuclear magnetic resonance data align with the morphinan skeleton: 1H NMR features signals for aromatic protons (δ ≈ 6.5–7.0 ppm), olefinic protons (δ ≈ 5.5–6.0 ppm), and the phenolic OH (broad, exchangeable). 13C NMR includes quaternary aromatic carbons (δ ≈ 110–150 ppm) and methoxy/allyl carbons. Exact assignments are derived from studies of derivatives but confirm the structure. Mass spectrometry typically shows a molecular ion at m/z 297 [M]+ (EI) or 298 [M+H]+ (ESI), with fragmentation patterns involving loss of the allyl side chain and phenolic cleavage, as observed in tandem MS of morphinans.

Natural Occurrence and Biosynthesis

Plant Sources and Content Levels

Oripavine occurs naturally in several of the genus Papaver, primarily (opium poppy), , and , where it accumulates in the of immature capsules and, to a lesser extent, other aerial tissues such as stems. In P. somniferum, the primary commercial source, oripavine constitutes a minor fraction of total alkaloids, which are concentrated in the capsule rather than seeds or roots. Concentrations vary by , , and environmental factors, but typical levels in capsule range from 0.009% to 0.057% (90–570 μg/g). In diverse collections of Papaver spp., absolute oripavine content reached up to 0.102 g/100 g dry weight (1.02 mg/g), representing 0–29.9% of total alkaloids in high-yielding accessions. In P. orientale and P. bracteatum, oripavine is a dominant , often exceeding and , with these historically explored as alternative sources due to their low content but higher phenolic morphinan yields. in P. somniferum has produced strains with elevated and oripavine, where these two combined can comprise over 50% of total alkaloids in , minimizing to below 1% for in pharmaceutical production. Such variations highlight genetic potential for optimization, though wild-type P. somniferum prioritizes (typically 8–14% dry weight in ), relegating oripavine to trace biosynthetic intermediates. Overall alkaloid profiles in capsules show oripavine accumulation peaking mid-development, influenced by factors like nutrients and , but empirical data underscore its consistently low baseline in standard cultivars compared to major alkaloids like (0.46–1.84%) or (0.08–0.30%).

Biosynthetic Pathway in Opium Poppy

In Papaver somniferum, oripavine arises in a minor branch of the morphine biosynthetic pathway, diverging from the primary route at , a key intermediate formed earlier via cyclization of salutaridinol 7-O-acetate by the enzyme thebaine synthase (CYP719B1). Thebaine undergoes regioselective O6-demethylation at the 6-position, catalyzed by the monooxygenase thebaine 6-O-demethylase (T6ODM, also known as CYP719B25), yielding oripavine as a phenolic with a free hydroxyl group at C6. This demethylation step parallels the 3-O-demethylation in the branch but occurs first at the 6-position, enabling the alternative progression to . Oripavine is then subjected to 3-O-demethylation by codeine O-demethylase (CODM, CYP275A24), producing morphinone, an unstable intermediate that is rapidly reduced to by codeinone reductase (COR), specifically the COR1 isoform capable of acting on both codeinone and morphinone substrates. This oripavine-dependent route bypasses and accounts for a smaller flux compared to the dominant thebaine-to-codeinone-to- sequence, though both converge on ; relative contributions vary by and environmental factors, with oripavine accumulating detectably (typically 0.1-1% of total alkaloids) in . The enzymes T6ODM and CODM localize primarily to sieve elements of the , where most late-stage BIA modifications occur, with finalization in adjacent laticifers via COR; this spatial separation ensures efficient precursor transport and minimizes intermediate leakage. Genetic studies confirm T6ODM's specificity for , as knockdowns reduce oripavine and downstream via this branch without disrupting the path. Oripavine also serves as a precursor for other minor phenanthrenes like neomorphine, though its primary role remains as a shunt in production.

Production Methods

Extraction from Natural Sources

Oripavine is primarily extracted from the of varieties genetically selected or mutagenized to contain elevated levels of oripavine and , with minimal and to facilitate purification. These varieties, such as the mutagenized "Norman" strain developed via treatment, yield oripavine at 0.43–0.74% by dry weight of straw, often comprising up to 95% of total alkaloids alongside when optimized. Commercial production, notably in by entities like Extractas Bioscience (formerly Tasmanian Alkaloids), relies on mature plant harvesting rather than collection from immature capsules, as the latter yields with lower oripavine concentrations. The extraction process begins with harvesting mature capsules and stems, followed by to remove seeds and produce dried . The is then moistened or softened with lime and to disrupt plant matrices, enabling countercurrent extraction using , dilute acids, , or . This yields a crude mixture, which undergoes liquid-liquid partitioning, often with , and adjustments to selectively precipitate or solubilize phenolics like oripavine. Further purification involves , , or chromatographic separation to isolate oripavine, producing concentrate of (CPS) suitable for downstream semi-synthesis. Tasmanian strains, first noted for significant oripavine in dried capsules in 1983, support efficient industrial scales due to their unique alkaloid profile. Yields and efficiency improve with low-morphine varieties, reducing purification costs; for instance, in optimized , and oripavine exceed 2% combined dry weight, enabling viable precursor production for opioids like . Analytical methods, such as for verification, confirm recoveries over 99% but are secondary to bulk industrial solvent processes.

Semi-Synthetic and Total Synthesis Routes

Oripavine is primarily accessed through semi-synthetic routes starting from naturally occurring opium alkaloids, particularly and , due to the challenges and inefficiencies of de novo construction. These methods leverage selective transformations to introduce the phenolic at the 3-position while preserving the moiety in ring C, which is essential for its reactivity in further derivatizations. A key semi-synthetic approach involves the selective 3-O-demethylation of using tri-sec-butylborohydride (L-Selectride) in at low temperature, yielding oripavine in 35% isolated yield after purification via crystallization of the oxalate salt from . This method, however, is limited by the high reactivity of thebaine's C-6 methyl ether, which promotes unwanted rearrangements and under demethylation conditions. An established alternative route begins with , where the dipotassium salt of its dianion undergoes selective O-methylation at the less hindered 6-position using methyl iodide, affording heterocodeine (3-hydroxy-6-methoxymorphinan) in greater than 90% yield. Acetylation of the 3-hydroxy group with , followed by dehydrogenation via oxidation with activated in , produces 3-O-acetyloripavine in 88% yield; subsequent base then liberates oripavine in 93% yield, achieving an overall conversion of 73% from . This sequence avoids the diene instability issues of thebaine-derived methods and has been applied in laboratory-scale preparations. Efforts to improve thebaine-to-oripavine conversion include catalytic processes reported in , which enable direct transformation under milder conditions to minimize side reactions, though specific yields and scalability details vary by protocol. These semi-synthetic strategies support industrial demands for oripavine as a precursor to analgesics like and , supplementing natural extraction where thebaine-rich cultivars provide the starting material. Total synthesis of oripavine remains unreported in peer-reviewed literature, as the complexity of assembling the morphinan tetracycle and its stereochemistry—typically requiring 20-30 steps with low overall yields—renders it impractical compared to semi-synthesis from abundant natural precursors. Adaptations of total syntheses for related morphinans, such as or , could theoretically extend to oripavine via analogous demethylation or oxidation steps, but no such extensions have been detailed.

Pharmacology

Receptor Binding and Mechanism of Action

Oripavine binds with moderate affinity to the μ-opioid receptor, exhibiting approximately 30- to 70-fold lower potency compared to . Like other compounds in the oripavine class, it demonstrates limited selectivity across the μ-, δ-, and κ-opioid receptor subtypes. These interactions occur at G-protein-coupled opioid receptors, where oripavine functions as an , primarily at the μ subtype, triggering downstream signaling that inhibits activity, promotes potassium efflux via Girk channels, and inhibits voltage-gated calcium channels, ultimately leading to neuronal hyperpolarization and suppression of pain-transmitting release. In vivo, oripavine's agonist activity manifests as antinociceptive effects in models, with analgesia peaking at 30 minutes post-administration and persisting for about 90 minutes across doses of 5, 10, and 20 mg/kg in mice. However, its pharmacological utility is constrained by associated excitatory effects, including convulsions observed at higher doses, which distinguish it from therapeutically viable agonists. Derivatives of oripavine, such as and , retain high-affinity binding but exhibit modified efficacy profiles, often as partial agonists or mixed agonist-antagonists, due to structural modifications at the 6,14-bridge or N-substituent.

In Vivo Effects and Toxicity Profile

In rodent models, oripavine demonstrates analgesic activity comparable to morphine via subcutaneous administration in the hot-plate test, with peak effects observed at 20 minutes post-injection and duration extending 40 to 60 minutes. This potency arises from its affinity for opioid receptors, particularly mu subtypes, though its therapeutic utility is severely limited by a narrow safety margin. Toxicity profiles in mice and rats reveal oripavine as a potent , with primary adverse effects including clonic-tonic seizures culminating in and death at doses approaching or exceeding thresholds. These neuroexcitatory symptoms are not antagonized by pretreatment (1 mg/kg), indicating mediation independent of classical activation, unlike typical mu-agonists. Non-oral LD50 values in exceed those of , underscoring greater acute lethality, though quantitative data remain sparse and insufficient for comprehensive characterization. Oripavine exhibits partial with but fails to mitigate withdrawal symptoms, further distinguishing its profile from standard opioids. Classification as an convulsant aligns with structural relatives like , emphasizing excitatory rather than purely in dynamics; empirical rodent data consistently prioritize this hazard over potential benefits, precluding clinical advancement. Limited human exposure reports, primarily via contaminated poppy seeds, yield no direct confirmation but highlight theoretical risks from metabolic conversion or additive burdens.

Derivatives and Applications

Key Semi-Synthetic Derivatives

Oripavine functions as a primary precursor for several semi-synthetic , particularly those in the 6,14-endoetheno- and 6,14-endoethano-oripavine classes, which feature a bridged structure formed via Diels-Alder reactions with suitable dienophiles. These modifications enhance binding affinity to opioid receptors, yielding compounds with exceptional potency. Etorphine, a full mu-opioid , is produced by reacting oripavine with cyclopentenyl derivatives, resulting in an analgesic potency approximately 1,000 to 10,000 times that of . This , developed in the , is employed mainly for large animal immobilization due to its rapid onset and short duration when antagonized. Buprenorphine, a partial mu-opioid with properties at kappa receptors, is synthesized from oripavine through N-demethylation followed by with cyclopropylmethyl groups on the bridged . It exhibits a ceiling effect on respiratory depression, making it suitable for and treatment, with sublingual around 30-50%. Diprenorphine, an oripavine-derived , is obtained similarly via bridged oripavine intermediates and serves to reverse the effects of potent agonists like , with a indicating high affinity for mu receptors. Other notable derivatives include dihydroetorphine, which mirrors etorphine's potency but with modified . These compounds underscore oripavine's versatility in generating therapeutics with tailored pharmacological profiles.

Pharmaceutical Uses of Derivatives

Buprenorphine, a semi-synthetic of oripavine, functions as a at the mu-opioid receptor with high affinity and low intrinsic activity, enabling its use in managing and cravings while exhibiting a ceiling effect on respiratory depression. The U.S. (FDA) approved for the treatment of in 2002, allowing office-based prescribing under the Drug Addiction Treatment Act, and it remains a cornerstone of medication-assisted treatment protocols. Additionally, is indicated for moderate to severe pain unresponsive to non-opioid therapies, available in formulations such as sublingual tablets, buccal films, patches, and extended-release injections. Etorphine, synthesized directly from oripavine via modifications at the 6,14-positions to form a bridged structure, is an ultrapotent full mu-opioid agonist approximately 1,000 to 80,000 times more potent than depending on the . It is approved solely for veterinary applications, primarily as an immobilizing agent for large mammals such as , rhinoceroses, and wild equids, where doses as low as 1-5 mg suffice for and analgesia during capture or medical procedures. Human use is contraindicated due to extreme potency and risk of fatal even from minimal exposure, such as skin contact with a single drop. Other oripavine-derived compounds, such as certain 6,14-bridged analogs, have been investigated for enhanced antinociceptive effects with reduced tolerance development, but none have achieved widespread pharmaceutical approval beyond contexts. The therapeutic utility of these derivatives stems from oripavine's structural scaffold, which facilitates modifications yielding agents with tailored receptor selectivity and pharmacokinetic profiles superior to natural alkaloids.

International Scheduling and Controls

Oripavine is listed in Schedule I of the , 1961, as amended by the 1972 Protocol. This scheduling, effective following a 2007 decision by the Commission on Narcotic Drugs (CND), subjects oripavine to strict international controls as a drug with potential for abuse and limited direct therapeutic use, though it serves as a precursor for semi-synthetic opioids. Prior to 2007, oripavine lacked explicit international scheduling despite domestic controls in some jurisdictions as a derivative, prompting the CND to address ambiguities under the convention. Under Schedule I provisions, parties to the convention must restrict oripavine production, manufacture, trade, and distribution to amounts necessary for medical and scientific purposes, determined via annual estimates submitted to the (INCB). and require from both exporting and importing countries, with detailed statistical returns on quantities moved and seized. The monitors compliance, noting a rising global manufacturing trend for oripavine—primarily for conversion to derivatives like —while urging vigilance against diversion due to its role in synthesis. These controls align oripavine with other opium alkaloids such as , emphasizing prevention of illicit production amid increasing legitimate demand for pharmaceutical precursors. Non-compliance can trigger INCB recommendations for corrective measures, though enforcement relies on national implementation, with no direct supranational penalties. Oripavine is not scheduled under the 1971 or the 1988 Convention against Illicit Traffic in Drugs and Psychotropic Substances as a precursor chemical, as its primary control stems from narcotic drug status rather than illicit manufacture facilitation.

National Regulations and Precursor Status

In the , oripavine is classified as a Schedule II under the , indicating a high potential for with accepted use primarily in the production of pharmaceutical derivatives such as . The formally designated it as a basic class of on September 24, 2007, effective December 10, 2007, under drug code 9660, building on prior control as a derivative. Annual aggregate production quotas are established by the DEA to limit supply to legitimate needs, with 2025 quotas proposed to reflect demand for semi-synthetic production. and export require DEA registration and reporting, with penalties for unauthorized handling aligned with Schedule II violations. In the , oripavine falls under Class A of the , subjecting it to the strictest controls due to its occurrence in poppy straw—a Class A substance—and its facile conversion to , another controlled . The Advisory Council on the Misuse of Drugs confirmed this classification in 2009, emphasizing compliance with the 1961 UN , under which oripavine was added to Schedule I in 2007. Licensing is required for any possession, production, or supply, with unlicensed activities carrying severe criminal penalties. In , oripavine is listed as a by the Office of Drug Control, regulated under the Narcotic Drugs Act 1967 to prevent diversion while permitting licensed cultivation of oripavine-rich opium poppies for export-oriented pharmaceutical production. Cultivation areas reached 1,394 hectares in 2022, reflecting its role as a source, but all activities demand authorization from state and federal authorities. As a precursor to potent semi-synthetic opioids like and , oripavine is subject to enhanced monitoring rather than standard synthetic precursor lists; for instance, the UK's ACMD has advocated its potential inclusion under drug precursor regulations (EC No 273/2004 and 111/2005) to address illicit conversion risks, though it remains primarily regulated as a nationally. In aligned jurisdictions, requires export/import certificates per UN conventions, with quotas tied to verified pharmaceutical demand.

Historical Context

Discovery and Early Characterization

Oripavine was first isolated in 1935 from , an Asiatic poppy species, by Russian chemists R. Konowalowa, S. Yunusoff, and A. Orekhov. Their extraction from plant material yielded the alkaloid as a major constituent, distinct from previously known opioids like and . This discovery highlighted P. orientale as a rich source, contrasting with its minor presence in . Initial characterization involved and tests, revealing an N-methyl group, a phenolic hydroxyl, and one O-methyl . Treatment with effected O-methylation at the phenolic position, yielding as the product and establishing oripavine as 3-O-demethyl. These findings positioned oripavine as a key biosynthetic intermediate related to , though its pharmacological properties remained unexplored at the time. The complete structural confirmation occurred in 1948 through degradative studies and comparative , solidifying its skeleton with a 6,7,8,14-tetradehydro-4,5-epoxy-3-hydroxy-6-methoxy-17-methyl configuration. Early quantitative assessments of P. orientale latex showed oripavine comprising about 20% of alkaloids, often co-occurring with 9% , underscoring its prevalence in non-opium poppies.

Evolution of Research and Production

Oripavine was first isolated in 1935 as a major from by a Russian team, who identified its N-methyl and O-methyl groups, marking its initial characterization within the class of . Early in the mid-20th century focused on its structural elucidation and role in biosynthesis, building on the broader understanding of pathways established decades prior, though oripavine remained a minor component in traditional extracts due to low natural yields in standard varieties. By the and , intensified chemical studies positioned oripavine as a key intermediate for semi-synthetic opioids, including the potent etorphine and buprenorphine, driving synthetic routes such as the 1975 development of methods to produce oripavine from and via demethylation and rearrangement. Biosynthetic advanced in 1988 with demonstrations of microbial transformation of to oripavine using Pseudomonas species, confirmed via , HPLC, and GCMS, highlighting enzymatic pathways that mirrored plant metabolism and opened avenues for biocatalytic production. Production evolved from incidental extraction in opium processing to targeted cultivation of high-yield varieties, spurred by pharmaceutical ; efforts began in the 1970s with strains like Ayra II yielding up to 3.5% (a direct precursor to oripavine), and accelerated in the 1990s through Tasmanian breeding programs emphasizing - and oripavine-rich P. somniferum to minimize content and streamline regulatory compliance. Mutagenized cultivars, such as the 'TOP 1' (thebaine oripavine poppy 1) developed by Tasmanian Alkaloids, further boosted yields, as patented in processes granted around 2002 for enhanced extraction from . Recent advancements include optimized biocatalytic conversions and for specific profiles, increasing global cultivation of oripavine-rich poppies by 26% from 2020 to 2021 to meet precursor needs for derivatives like and .

References

  1. https://www.sciencedirect.com/topics/chemistry/oripavine
  2. https://pubchem.ncbi.nlm.nih.gov/compound/Oripavine
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC10154933/
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC7009406/
  5. https://antheia.bio/wp-content/uploads/2023/08/Oripavine_Product-Sheet.pdf
  6. https://www.sciencedirect.com/topics/neuroscience/oripavine
  7. https://www.federalregister.gov/documents/2007/09/24/E7-18524/designation-of-oripavine-as-a-basic-class-of-controlled-substance
  8. https://precision.fda.gov/ginas/app/ui/substances/7de8ccb9-9e82-4be6-aefe-8266cffd8eee
  9. https://www.scirp.org/journal/paperinformation?paperid=47948
  10. https://pdspdb.unc.edu/kidb2/kidb/web/manage/test-ligands/view?test_ligand_id=8596
  11. https://cdnsciencepub.com/doi/pdf/10.1139/v88-393
  12. https://pubs.acs.org/doi/10.1021/jm00245a006
  13. https://www.drugfuture.com/chemdata/oripavine.html
  14. https://pmc.ncbi.nlm.nih.gov/articles/PMC2492654/
  15. https://www.sciencedirect.com/science/article/pii/S1044030503005397
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC9943628/
  17. https://dergipark.org.tr/en/pub/jaefs/issue/65546/796695
  18. https://www.nature.com/articles/s41598-021-04056-3
  19. https://www.sciencedirect.com/topics/medicine-and-dentistry/oripavine
  20. https://patents.google.com/patent/US6067749A/en
  21. https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2011.2405
  22. https://link.springer.com/article/10.1007/s00425-014-2056-8
  23. https://academic.oup.com/plcell/article/25/10/4110/6099535
  24. https://www.mdpi.com/2223-7747/14/10/1413
  25. https://patents.google.com/patent/US6376221B1/en
  26. https://patents.google.com/patent/US6723894B2/en
  27. https://www.jstage.jst.go.jp/article/cpb/53/11/53_11_1446/_article
  28. https://pubmed.ncbi.nlm.nih.gov/1177252/
  29. https://onlinelibrary.wiley.com/doi/10.1002/adsc.201400445
  30. https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2018.5243
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC3799236/
  32. https://pubs.acs.org/doi/10.1021/jm401964y
  33. https://pubmed.ncbi.nlm.nih.gov/6121539/
  34. https://www.sciencedirect.com/topics/medicine-and-dentistry/morphinan-derivative
  35. https://www.mdpi.com/1422-0067/26/6/2736
  36. https://www.sciencedirect.com/science/article/pii/S0022356525219048
  37. https://sk.sagepub.com/ency/edvol/download/drugpolicy/chpt/synthetic-narcotics.pdf
  38. https://www.researchgate.net/publication/265332625_Recent_Advances_in_the_Chemistry_of_Oripavine_and_Its_Derivatives
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC2581407/
  40. https://www.fda.gov/news-events/press-announcements/fda-approves-new-buprenorphine-treatment-option-opioid-use-disorder
  41. https://go.drugbank.com/drugs/DB00921
  42. https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1967.tb02108.x
  43. https://go.drugbank.com/drugs/DB01497
  44. https://www.sciencedirect.com/topics/medicine-and-dentistry/etorphine
  45. https://pubmed.ncbi.nlm.nih.gov/21863064/
  46. https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2024/Narcotics_2024_EN.pdf
  47. https://docs.un.org/en/E/CN.7/2007/10
  48. https://www.federalregister.gov/documents/2005/12/13/05-23958/international-drug-scheduling-convention-on-psychotropic-substances-single-convention-on-narcotic
  49. https://www.unodc.org/pdf/convention_1961_en.pdf
  50. https://www.federalregister.gov/documents/2007/12/10/E7-23759/designation-of-oripavine-as-a-basic-class-of-controlled-substance-correction
  51. https://www.regulations.gov/document/DEA-2024-0120-0001
  52. https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf
  53. https://assets.publishing.service.gov.uk/media/5a7a394de5274a34770e5223/oripavine.pdf
  54. https://www.gov.uk/government/publications/acmd-letter-to-the-home-secretary-on-the-consideration-of-oripavine
  55. https://www.odc.gov.au/controlled-substances/list/oripavine
  56. https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2022/3_NAR_2022-Part_3_Supply_and_Demand_E.pdf
  57. https://www.mdpi.com/1420-3049/27/9/2863
  58. https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1950-01-01_2_page004.html
  59. https://www.sciencedirect.com/science/article/pii/S0022354915404022
  60. https://www.pnas.org/doi/10.1073/pnas.85.4.1267
  61. https://www.sciencedirect.com/science/article/abs/pii/S037907380700610X
  62. https://www.researchgate.net/publication/300623271_Opium_Poppy_Genetic_Upgradation_Through_Intervention_of_Plant_Breeding_Techniques
  63. https://cdnsciencepub.com/doi/10.1139/cjc-2014-0552
Add your contribution
Related Hubs
Contribute something
User Avatar
No comments yet.