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The 4″-fluoro analogue (i.e., substituted on the [[phenethyl]] ring) of the 3R,4S,βS isomer of ohmefentanyl is one of the most potent [[opioid]] agonists yet discovered, possessing an [[analgesic]] potency approximately 18,000 times that of morphine.<ref>{{cite journal | first1=Z. | last1=Yong | url=http://www.ingentaconnect.com/contentone/govi/pharmaz/2003/00000058/00000005/art00002 | title=Synthesis and analgesic activity of stereoisomers of cis-fluoro-ohmefentanyl | last2=Hao | first2=W. | last3=Weifang | first3=Y. | last4=Qiyuan | first4=D. | last5=Xinjian | first5=C. | last6=Wenqiao | first6=J. | last7=Youcheng | first7=Z. | journal=Die Pharmazie | date=May 2003 | volume=58 | issue=5 | pages=300–302 | pmid=12779044}}</ref> Other analogues with potency higher than that of ohmefentanyl itself include the 2′-fluoro derivative (i.e., substituted on the aniline phenyl ring), and derivatives where the N-propionyl group was replaced by N-methoxyacetyl or 2-furamide groups, or a carboethoxy group is added to the 4-position of the piperidine ring. The latter is listed as being up to 30,000 times more potent than morphine.<ref>{{cite journal | title=Ohmefentanyl and its stereoisomers: Chemistry and pharmacology | vauthors=Brine GA,Carroll FI, Richardson-Leibert TM,Xu H,Rothman RB | journal=Current Medicinal Chemistry | date=August 1997 | volume=4 | issue=4 | pages=247–270 | issn=0929-8673}}</ref>
The 4″-fluoro analogue (i.e., substituted on the [[phenethyl]] ring) of the 3R,4S,βS isomer of ohmefentanyl is one of the most potent [[opioid]] agonists yet discovered, possessing an [[analgesic]] potency approximately 18,000 times that of morphine.<ref>{{cite journal | first1=Z. | last1=Yong | url=http://www.ingentaconnect.com/contentone/govi/pharmaz/2003/00000058/00000005/art00002 | title=Synthesis and analgesic activity of stereoisomers of cis-fluoro-ohmefentanyl | last2=Hao | first2=W. | last3=Weifang | first3=Y. | last4=Qiyuan | first4=D. | last5=Xinjian | first5=C. | last6=Wenqiao | first6=J. | last7=Youcheng | first7=Z. | journal=Die Pharmazie | date=May 2003 | volume=58 | issue=5 | pages=300–302 | pmid=12779044}}</ref> Other analogues with potency higher than that of ohmefentanyl itself include the 2′-fluoro derivative (i.e., substituted on the aniline phenyl ring), and derivatives where the N-propionyl group was replaced by N-methoxyacetyl or 2-furamide groups, or a carboethoxy group is added to the 4-position of the piperidine ring. The latter is listed as being up to 30,000 times more potent than morphine.<ref>{{cite journal | title=Ohmefentanyl and its stereoisomers: Chemistry and pharmacology | vauthors=Brine GA,Carroll FI, Richardson-Leibert TM,Xu H,Rothman RB | journal=Current Medicinal Chemistry | date=August 1997 | volume=4 | issue=4 | pages=247–270 | issn=0929-8673}}</ref>


Side effects of [[fentanyl]] analogues are similar to those of fentanyl itself, which include [[itching]], [[nausea]] and potentially serious [[respiratory depression]], which can be life-threatening. Fentanyl analogues have killed hundreds of people throughout Europe and the former Soviet republics since the most recent resurgence in use began in [[Estonia]] in the early 2000s, and novel derivatives continue to appear.<ref>{{cite journal |vauthors=Mounteney J, Giraudon I, Denissov G, Griffiths P | title=Fentanyls: Are we missing the signs? Highly potent and on the rise in Europe | date=July 2015 | journal=International Journal of Drug Policy | volume=26 | issue=7 | pages=626–631 | doi=10.1016/j.drugpo.2015.04.003 | pmid=25976511}}</ref>
Side effects of [[fentanyl]] analogues are similar to those of fentanyl itself, which include [[itching]], [[nausea]] and potentially serious [[respiratory depression]], which can be life-threatening. Illicitly used fentanyl analogues have killed hundreds of people throughout Europe and the former Soviet republics since the most recent resurgence in use began in [[Estonia]] in the early 2000s, and novel derivatives continue to appear.<ref>{{cite journal |vauthors=Mounteney J, Giraudon I, Denissov G, Griffiths P | title=Fentanyls: Are we missing the signs? Highly potent and on the rise in Europe | date=July 2015 | journal=International Journal of Drug Policy | volume=26 | issue=7 | pages=626–631 | doi=10.1016/j.drugpo.2015.04.003 | pmid=25976511}}</ref>


[[File:OMF.png|right|thumb|300px|Molecular structure of four ohmefentanyl isomers]]
[[File:OMF.png|right|thumb|300px|Molecular structure of four ohmefentanyl isomers]]

Revision as of 08:42, 16 June 2020

Ohmefentanyl
Clinical data
ATC code
  • none
Legal status
Legal status
Identifiers
  • N-[1-(2-hydroxy-2-phenylethyl)-3-methylpiperidin-4-yl]-N-phenylpropanamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H30N2O2
Molar mass366.497 g/mol g·mol−1
3D model (JSmol)
  • CCC(=O)N(c1ccccc1)C2CCN(CC2C)CC(O)c3ccccc3
  • InChI=1S/C23H30N2O2/c1-3-23(27)25(20-12-8-5-9-13-20)21-14-15-24(16-18(21)2)17-22(26)19-10-6-4-7-11-19/h4-13,18,21-22,26H,3,14-17H2,1-2H3 checkY
  • Key:FRPRNNRJTCONEC-UHFFFAOYSA-N checkY
  (verify)

Ohmefentanyl (also known as β-hydroxy-3-methylfentanyl, OMF and RTI-4614-4)[1] is an extremely potent opioid analgesic drug which selectively binds to the µ-opioid receptor.[2][3]

Ohmefentanyl is one of the most potent μ-opioid receptor agonists known, comparable to super-potent opioids such as carfentanil and etorphine which are only legally used for tranquilizing large animals such as elephants in veterinary medicine. In mouse studies, the most active isomer 3R,4S,βS-ohmefentanyl was 28 times more powerful as a painkiller than fentanyl, the chemical from which it is derived, and 6300 times more powerful than morphine.[4][5][6][7] Ohmefentanyl has three stereogenic centers and eight stereoisomers, which are named F9201–F9208. Researchers are studying the different pharmaceutical properties of these isomers.[8]

The 4″-fluoro analogue (i.e., substituted on the phenethyl ring) of the 3R,4S,βS isomer of ohmefentanyl is one of the most potent opioid agonists yet discovered, possessing an analgesic potency approximately 18,000 times that of morphine.[9] Other analogues with potency higher than that of ohmefentanyl itself include the 2′-fluoro derivative (i.e., substituted on the aniline phenyl ring), and derivatives where the N-propionyl group was replaced by N-methoxyacetyl or 2-furamide groups, or a carboethoxy group is added to the 4-position of the piperidine ring. The latter is listed as being up to 30,000 times more potent than morphine.[10]

Side effects of fentanyl analogues are similar to those of fentanyl itself, which include itching, nausea and potentially serious respiratory depression, which can be life-threatening. Illicitly used fentanyl analogues have killed hundreds of people throughout Europe and the former Soviet republics since the most recent resurgence in use began in Estonia in the early 2000s, and novel derivatives continue to appear.[11]

Molecular structure of four ohmefentanyl isomers

Synthesis

The synthesis of ohmefentanyl is more complex than the synthesis of fentanyl and some of its related analogues, requiring more reagents, equipment, and time compared to the synthesis of fentanyl. The synthesis of ohmefentanyl is accomplished starting from 1-Benzyl-3-methyl-4-piperidinone from which the imine is formed by reaction with aniline. The obtained imine is reduced using sodium borohydride to yield the amine which is then reacted with propionic anhydride. In the next step of the synthesis, the benzyl protecting group is removed from the piperidine ring by catalytic hydrogenation to give the secondary amine which is then reacted with 2-bromoacetophenone, after which the ketone is reduced with sodium borohydride to form ohmefentanyl. Ohmefentanyl Synthetic Pathway

See also

References

  1. ^ Rothman, R. B.; Heng Xu; Seggel, M.; Jacobson, A. E.; Rice, K. C.; Brine, G. A.; Carroll, F. I. (April 1991). "RTI-4614-4: An analog of (+)-cis-3-methylfentanyl with a 27,000-fold binding selectivity for mu versus delta opioid binding sites". Life Sciences. 48 (23): PL111–PL116. doi:10.1016/0024-3205(91)90346-D. PMID 1646357.
  2. ^ Brine, G. A.; Stark, P. A.; Liu, Y.; Carroll, F. I.; Singh, P.; Xu, H.; Rothman, R. B. (1995). "Enantiomers of Diastereomeric cis-N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamides: Synthesis, X-ray Analysis, and Biological Activities". Journal of Medicinal Chemistry. 38 (9): 1547–1557. doi:10.1021/jm00009a015. PMID 7739013.
  3. ^ Wang, Z. X.; Zhu, Y. C.; Jin, W. Q.; Chen, X. J.; Chen, J.; Ji, R. Y.; Chi, Z. Q. (September 1995). "Stereoisomers of N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]- N-phenylpropanamide: Synthesis, Stereochemistry, Analgesic Activity, and Opioid Receptor Binding Characteristics". Journal of Medicinal Chemistry. 38 (18): 3652–3659. doi:10.1021/jm00018a026. PMID 7658453.
  4. ^ H. D. Banks, C. P. Ferguson (September 1988). "The Metabolites of Fentanyl and its Derivatives" (PDF). U.S. Army Chemical Research, Development and Engineering Center, Aberdeen Proving Ground, MD.
  5. ^ Jin, W. Q.; Xu, H.; Zhu, Y. C.; Fang, S. N.; Xia, X. L.; Huang, Z. M.; Ge, B. L.; Chi, Z. Q. (May 1981). "Studies on synthesis and relationship between analgesic activity and receptor affinity for 3-methyl fentanyl derivatives". Scientia Sinica. 24 (5): 710–720. PMID 6264594.
  6. ^ Zhu, Y. C.; Wu, R. Q.; Chou, D. P.; Huang, Z. M. (December 1983). "Studies on potent analgesics. VII. Synthesis and analgesic activity of diastereoisomers of 1-beta-hydroxy-3-methylfentanyl (7302) and related compounds". Yao Xue Xue Bao = Acta Pharmaceutica Sinica. 18 (12): 900–904. PMID 6679170.
  7. ^ Guo, G. W.; He, Y.; Jin, W. Q.; Zou, Y.; Zhu, Y. C.; Chi, Z. Q. (June 2000). "Comparison of physical dependence of ohmefentanyl stereoisomers in mice". Life Sciences. 67 (2): 113–120. doi:10.1016/S0024-3205(00)00617-2. PMID 10901279.
  8. ^ Liu, Z.; He, Y.; Jin, W.; Chen, X.; Shen, Q.; Chi, Z. (April 2004). "Effect of chronic treatment of ohmefentanyl stereoisomers on cyclic AMP formation in Sf9 insect cells expressing human μ-opioid receptors". Life Sciences. 74 (24): 3001–3008. doi:10.1016/j.lfs.2003.10.027. PMID 15051423.
  9. ^ Yong, Z.; Hao, W.; Weifang, Y.; Qiyuan, D.; Xinjian, C.; Wenqiao, J.; Youcheng, Z. (May 2003). "Synthesis and analgesic activity of stereoisomers of cis-fluoro-ohmefentanyl". Die Pharmazie. 58 (5): 300–302. PMID 12779044.
  10. ^ Brine GA, Carroll FI, Richardson-Leibert TM, Xu H, Rothman RB (August 1997). "Ohmefentanyl and its stereoisomers: Chemistry and pharmacology". Current Medicinal Chemistry. 4 (4): 247–270. ISSN 0929-8673.
  11. ^ Mounteney J, Giraudon I, Denissov G, Griffiths P (July 2015). "Fentanyls: Are we missing the signs? Highly potent and on the rise in Europe". International Journal of Drug Policy. 26 (7): 626–631. doi:10.1016/j.drugpo.2015.04.003. PMID 25976511.
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