Ohmefentanyl

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Structural formula
Structural formula of ohmefentanyl
Structural formula without specifying the stereochemistry
(mixture of several stereoisomers)
General
Surname Ohmefentanyl
other names

N - [1- (2-hydroxy-2-phenyl-ethyl] -3-methyl-4-piperidyl) - N -phenyl-propanamide

Molecular formula C 23 H 30 N 2 O 2
Brief description

colorless powder

External identifiers / databases
CAS number 78995-14-9
PubChem 10474095
Wikidata Q905028
properties
Molar mass 366.497 g mol −1
Physical state

firmly

safety instructions
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ohmefentanyl (β-hydroxy-3-methylfentanyl) was synthesized as a mixture of isomers in China in the second half of the 1970s and was first mentioned in the scientific literature in 1981. There are a total of 8 isomers of ohmefentanyl, which differ considerably in their effect and are referred to in the specialist literature as F9201 to F9208. The effect of the individual isomers was intensively investigated in the 1980s and especially the 1990s. The most potent isomer is (+) - (3 R , 4 S , 2` S ) -ohmefentanyl (F9204), which, as an analgesic, is 6,200–13,000 times the potency of morphine. In opioid-dependent monkeys, F9204 even reaches 20,000–50,000 times the potency of morphine (complete suppression of the withdrawal syndrome).

The individual isomers differ considerably in their physical addictive potential, i.e. H. in their ability to induce physical dependence at doses that are comparable in analgesic effectiveness. It should be noted that the most potent and most effective isomer F9204 of all isomers has the lowest physical addictiveness, which is also significantly lower than with morphine under comparable doses. An analgesic inactive isomer (F9203) can also cause physical dependence if given chronically. Because of these unusual properties, ohmefentanyl isomers (similar to dihydroetorphine) are used in experimental pharmacology to study the biochemical mechanisms of opioid dependence. Ohmefentanyl binds selectively to the µ-opioid receptor . Despite its enormous potency, it has not yet played a role in veterinary medicine (in contrast to carfentanil ) .

The 4 "fluorine analog (ie the fluorine atom was inserted on the phenethyl ring) of the (3 R , 4 S , 2 S ) isomer is even stronger, with an analgesic potency 18,000 times that of morphine With a carboethoxy group in the fourth position of the piperidine ring, ohmefentanyl would be up to 30,000 times stronger pain reliever than morphine.

Physical Addiction Potency of Ohmefentanyl Isomers: Biochemical Backgrounds and Stereochemical Differences

The biochemical mechanisms that underlie the development of physical dependence on chronic opioid use are complex and only partially understood to this day. However, research over the last 25 years has produced significant findings that can partially explain various phenomena of opioid dependence. A significant mechanism of the development of dependency with chronic opioid administration is the upregulation or supersensitization of the adenylate cyclase . The biochemical mechanisms on which this upregulation and supersensitization is based are complex and not yet fully understood. Depending on the exact (stereo) structure of the opioid, up to eight types of adenylate cyclase are regulated differently under acute or chronic opioid administration. With acute administration, some types are inhibited via inhibitory opioid receptors (activation of G i / o proteins) and are upregulated during chronic opioid administration, with other types the opposite is true. In addition, adenylate cyclase is stimulated via excitatory opioid receptors (activation of G s proteins). Chronic opioid administration unbalances the balance between inhibition, activation and also activity of adenylate cyclase. When the opioid is withdrawn (or a provocation test with the opioid antagonist naloxone), the inhibitory effect is no longer applicable and an excess of cAMP results. In the case of the ohmefentanyl isomers, the ability to provoke a cAMP excess (i.e. a deregulation of the adenylate cyclase) through chronic application and subsequent administration of naloxone varies greatly. The most analgesic isomer F9204 has a 2.7 times higher receptor binding affinity and a 4.3 times higher analgesic potency than the isomer F9202 (ED 50 = 1.06 µg / kg: 4.6 µg / kg), F9202 but 140 times higher physical addiction potency than F9204 (cumulative ED 50 : 98.4 µg / kg: 0.7 µg / kg; test method: withdrawal jumping in mice after administration of naloxone).

In cell cultures, F9202 is 71.5 times more potent than F9204 with regard to upregulation of adenylate cyclase. While F9204 is an opioid with a comparatively low physical addiction potential (less than morphine), isomer F9202 is an opioid with an extremely high physical addiction potential (stronger than morphine), relative to the analgesic potency. These results show that the analgesic effect and the induction of physical dependence are partly based on different mechanisms. The situation is similar with dihydroetorphin, which in its analgesic potency is comparable to ohmefentanyl-F9204. According to animal experiments and findings from human medicine, dihydroetorphine has a significantly lower physical addiction potential than morphine, although it is up to 100,000 times more potent than morphine in opioid-dependent monkeys. Dihydroetorphine (and etorphine) also have a much lower potency than morphine to cause upregulation and supersensitization of adenylate cyclase with chronic administration. With dihydroetorphine, physical opioid dependence can be achieved in a period of 7 to 14 days, in contrast to the methods previously used (tapering off methadone, switching to buprenorphine and tapering off buprenorphine or using alpha agonists such as clonidine or lofexidine) quite easily and without significant occurrence physical withdrawal symptoms are ended. It is noteworthy that after a 7-14 day substitution phase immediately after discontinuation (tapering) of dihydroetorphine, a naloxone provocation test remains negative (or only a minimal rebound is recorded), while one days later after discontinuation of classic opioids violent reaction to naloxone ensues.

The unusual effect of dihydroetorphin is based, among other things, on the selective blocking of the G s -coupled, excitatory µ-opioid receptors - with simultaneous activation of inhibitory receptors, while without exception all medically used opioids have a bimodal effect and activate both inhibitory and excitatory receptors and the latter with chronic opioid administration experience supersensitization. Supersensitization of the excitatory receptors is an important key mechanism of opioid dependence, referred to in the literature as "excitatory supersensitivity". However, it is not yet known whether the lower addictive potential of ohmefentanyl-F9204, as with dihydroetorphin, is also based on a selective blockage of excitatory opioid receptors.

Ohmefentanyl isomers: analgesic ED 50 , analgesic potency (morphine = 1), cumulative ED 50 (to induce physical addiction) and addiction index compared to morphine

Isomer code configuration analgesic ED 50 (µg / kg) (A) power cumulative ED 50 (µg / kg) (B) Dependency Index (B / A)
F9201 (+) - cis - (3 S , 4 R , 2 S ) 10,000 0.68 > 60,000 > 6
F9202 (-) - cis - (3 R , 4 S , 2 R ) 4.6 1478 0.7 0.15
F9203 (-) - cis - (3 S , 4 R , 2 R ) > 10,000 <0.68 9941 <1
F9204 (+) - cis - (3 R , 4 S , 2 S ) 1.06 6415 98.1 92.8
F9205 (+) - trans - (3 S , 4 S , 2 S ) 14th 486 30.3 2.1
F9206 (-) - trans - (3 R , 4 R , 2 R ) 72 94 361 5.0
F9207 (+) - trans - (3 S , 4 S , 2 R ) 75 91 383 5.1
F9208 (-) - trans - (3 R , 4 R , 2 S ) 9.7 701 44.5 4.6
Morphine - 6800 1 513,000 75.4

Ohmefentanyl isomers: µ-receptor binding affinity and EC 50 value for the induction of a naloxone-provoked cAMP excess (50% of the maximum)

Isomer code configuration Bond K i (nM) (A) cAMP excess, EC 50 (nM) (B) Dependency Index (A / B)
F9202 (-) - cis - (3 R , 4 S , 2 R ) 4.47 ± 1.08 5.02 ± 2.36 0.89
F9204 (+) - cis - (3 R , 4 S , 2 S ) 1.66 ± 0.28 359 ± 65 0.0046
F9205 (+) - trans - (3 S , 4 S , 2 S ) 3.71 ± 1.25 16.5 ± 13.0 0.22
F9206 (-) - trans - (3 R , 4 R , 2 R ) 16.7 ± 2.0 318 ± 60 0.053
F9207 (+) - trans - (3 S , 4 S , 2 R ) 29.9 ± 4.1 520 ± 75 0.058
F9208 (-) - trans - (3 R , 4 R , 2 S ) 4.00 ± 0.1 80.1 ± 0.2 0.050

Mental addictive potential of ohmefentanyl isomers: positive reinforcement ( reinforcement )

In relation to the analgesic dose, all ohmefentanyl isomers have a lower psychological addiction potential than morphine in mice (test method: conditioned place preference). From this it can be concluded that the psychological effects that induce abuse (relaxation, feeling of satisfaction, euphoria) are less pronounced than with morphine.

Ohmefentanyl isomers: ED 50 (analgesia), analgesic potency (morphine = 1), ED 50 (conditioned place preference) and dependency index compared to morphine

Isomer code configuration analgesic ED 50 (µg / kg) (A) power Place preference ED 50 (µg (kg) (B) Dependency Index (A / B)
F9202 (-) - cis - (3 R , 4 S , 2 R ) 4.6 1478 7th 0.66
F9204 (+) - cis - (3 R , 4 S , 2 S ) 1.06 6415 2 0.53
F9205 (+) - trans - (3 S , 4 S , 2 S ) 14th 486 32 0.44
F9206 (-) - trans - (3 R , 4 R , 2 R ) 72 94 192 0.38
F9207 (+) - trans - (3 S , 4 S , 2 R ) 75 91 157 0.48
F9208 (-) - trans - (3 R , 4 R , 2 S ) 9.7 701 30th 0.32
Morphine - 6800 1 5300 1.28

Individual evidence

  1. ↑ a b Clearsynth: ( page no longer available , search in web archives: Ohmefentanyl ) (PDF; 582 kB)@1@ 2Template: Dead Link / www.clearsynth.com
  2. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  3. ↑ George A. Brine, Peter A. Stark, Young Liu, F. Ivy Carrol, P. Singh et al. Enantiomers of Diastereomeric cis-N- [1- (2-Hydroxy-2-phenylethyl) -3-methyl-4-piperidyl ] -N-phenylpropanamides: Synthesis, X-ray Analysis, and Biological Activities. In: Journal of Medicinal Chemistry . Vol. 38, # 9, 1995, pp. 1547-1557.
  4. ^ GW Guo, Y. He, WQ Jin, Y. Zou, YC Zhu, ZQ Chi: Comparison of physical dependence of ohmefentanyl stereoisomers in mice. In: Life Sciences . 67 (2), 2000, pp. 113-120.
  5. ↑ Z. Yong, W. Hao, Y. Weifang, D. Qiyuan, C. Xinjian, J. Wenqiao, Z. Youcheng: Synthesis and analgesic activity of stereoisomers of cis-fluoro-ohmefentanyl. In: The Pharmacy . 58 (5), 2003, pp. 300-302.
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  10. ↑ a b c G. W. Guo, Y. He, WQ Jin, Y. Zou, YC Zhu, ZQ Chi: Comparison of physical dependence of ohmefentanyl stereoisomers in mice . In: Life Science . tape 67 , no. 2 , 2000, pp. 113-120 , doi : 10.1016 / S0024-3205 (00) 00617-2 , PMID 10901279 .
  11. ↑ a b c Z. H. Liu, Y. He, WQ Jin, XJ Chen, QX Shen, ZQ Chi: Effect of chronic treatment of ohmefentanyl stereoisomers of cyclic AMP formation in Sf9 insect cells expressing human µ-opioid receptors . In: Life Science . tape 74 , no. 24 , 2004, pp. 3001-3008 , doi : 10.1016 / j.lfs.2003.10.027 .
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  13. ↑ BY Qin, M. Huang, YC Zhang, H. Miao: Comparision of the dependence potential of Dihydroetorphine, Etorphine an Morphine . In: Regulatory Peptides . tape 54 , no. 1 , 1994, p. 237-238 , doi : 10.1016 / 0167-0115 (94) 90477-4 .
  14. ↑ M. Huang, DX Wang, BY Qin: Dihydroetorphine, a potent opioid with low dependence potential . In: Regulatory Peptides . tape 53 , Suppl. 1, 1994, pp. 81-82 , doi : 10.1016 / 0167-0115 (94) 90251-8 .
  15. ^ MD Aceto, LS Harris, ER Bowman: Etorphines: µ-opioid receptor-selective antinociception and low physical dependence capacity . In: European Journal of Pharmacology . tape 338 , no. 3 , 1997, p. 215-223 , doi : 10.1016 / S0014-2999 (97) 81924-3 , PMID 9424015 .
  16. ^ A b B. Y. Qin, DX Wang, M. Huang: The application of Dihydroetorphine to detoxification of Heroin addicts . In: Regulatory Peptides . tape 53 , Suppl. 1, 1994, pp. 293-294 , doi : 10.1016 / 0167-0115 (94) 90353-0 .
  17. ↑ a b c B. Y. Qin: Advances in dihydroetorphine: From analgesia to detoxification . In: Drug Development Research . tape 39 , no. 2 , 1996, p. 113-120 , doi : 10.1002 / (SICI) 1098-2299 (199610) 39: 2 <131 :: AID-DDR3> 3.0.CO; 2-Q .
  18. ↑ JG Liu, ZH Gong, BY Qin: Effects of opioid receptor agonists on cAMP second messenger system . In: Zhongguo Yao Li Xue Bao . tape 20 , no. 5 , 1999, p. 452-456 , PMID 10678096 .
  19. ↑ a b K. F. Shen, SM Crain: Etorphine Elicits Unique Inhibitory-Agonist and Excitatory-Antagonist Actions at Opioid Receptors on Sensory Neurons: New Rationale for Improved Clinical Analgesia and Treatment of Opiate Addiction . In: NIDA Research Monograph . tape 147 , 1995, pp. 234-268 .
  20. ↑ KF Shen, SM Crain: Antagonists at excitatory opioid receptors on sensory neurons in culture increase potency and specificity of opiate analgesics and attenuate development of tolerance / dependence . In: Brain Research . tape 636 , no. 2 , 1994, p. 286-297 , doi : 10.1016 / 0006-8993 (94) 91028-6 , PMID 8012813 .
  21. ↑ a b G. W. Guo, ZH Liu, WQ Jin, HP Zhang, XJ Chen, YC Zhu, ZQ Chi: Quantitative comparison of ohmefentanyl isomers induced conditioning place preference in mice . In: Life Science . tape 68 , no. 21 , 2001, p. 2383-2390 , doi : 10.1016 / S0024-3205 (01) 01030-X , PMID 1350009 .