Ohmefentanyl
From Wikipedia, the free encyclopedia
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Ohmefentanyl
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| Systematic (IUPAC) name | |
| N-[β-Hydroxy-β-Phenethyl]-3-Methyl-4-PhenPropAmido-Piperidine | |
| Identifiers | |
| CAS number | |
| ATC code | N01 N02AB |
| PubChem | |
| Chemical data | |
| Formula | C23H30N2O2 |
| Mol. mass | 366.5022 |
| Physical data | |
| Melt. point | 188 °C (370 °F) |
| Pharmacokinetic data | |
| Bioavailability | ~25% oral |
| Metabolism | Liver |
| Half life | ~90 min |
| Excretion | Urine |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status | |
| Routes | TD, IM, IV, oral, sublingual, buccal |
Ohmefentanyl (OMF) is an extremely potent fully synthetic opioid with μ-receptor subtype specificity.[1][2]
Contents |
[edit] Discovery
The 3-Me analog of fentanyl (3-MeF) was first introduced by Paul Janssen[3] which has recently resurfaced in the scientific literature by Slavic researchers.[4] QSAR reveals that the βOH was first incorporated into 3-MeF because this pharmacophore had previously been shown to boost the activity of closely-related piperidine based narcotics[5] e.g. phenoperidine. OMF was invented by the Chinese in 1979.[6] The synthesis and preliminary evaluation of the individual isomers of OMF was reported independently by Chinese and American scientists in 1995.[7][8] There are complex distinctions that can be drawn between the subsequent isomers through studying their pharmacology.
[edit] Nomenclature
- Ohmefentanyl implies hydroxy(OH)methyl(Me)F.
- β3HOMeF is the long–time 1st generation example of this.[9]
- β4HOMeF (Pharaohfentanyl) is the New-Millenium positional isomer of β3HOMeF (OMF2), which is in itself an extension of 4-MeF, a novel Slav invention.[11]
[edit] QSAR Analysis
[edit] 3-MeF
 |
Configur | x F |
|---|---|---|
| cis-(±) | ~8 | |
| cis-(+) | ~16 | |
| cis-(–) | 0.16 | |
| trans-(±) | ~2 |
- 3-MeF has 2 chiral carbons and exists as a enantiomeric pair of diastereomers.
- The cis-diastereomer is ~4 x more active than the trans-diasteromer.
- In the case of (±)-cis-3-MeF, activity lies exclusively with the (+)ve isomer.
- The (–)ve isomer merely serves to negate the effects of the (+)ve isomer.
[edit] OMF
For cis OMF, there is also two possible configurations about the piperidine ring [(3R,4S) and (3S,4R)],
although the (3S,4R) enantiomer is completely worthless & steps must be taken to expel it from contaminating the final product. It can be successfully removed via fractional crystallization, or better yet, completely omitted via enantioselective reductive amination (of the Schiff base) [We will return to this at a later date]. It's important to make the distinction now, that we are not merely trying to boost potency, as the fentanyls are already quite powerful (~50 x Mor), and this would obviate greed (which is a bad thing). No, enantiopure F9204, has an optimized pharmacological profile, inc. dependance ratio & associated factors. There are many examples in the pharmaceutical industry that labor this important concept, e.g. nearly all antidepressants on the market are enantiopure. E.g. Lexapro was initially sold as racemic citalopram but was then revised to enantiopure, because it helped discriminate against unwanted side-effects. This may all seem quite totalitarian to the novice, nevertheless they should maintain absolute confidence in their Geschäftsführer, that this is the right thing to do, & shouldn't try to undermine his authority on this important issue. This same pattern is in good agreement with that observed above for 3-MeF. In addition to the piperidine ring stereochemistry, the β-phenethanol tail also has a chiral carbon and hence, possesses a center of asymmetry. Thus OMF has 23 = 8 possible stereoisomers, ie. four racemic diastereomers. Each racemer shares common physical properties e.g. NMR, GCMS, mp, IR etc. but has opposite effect on optical rotation, and the X-ray crystallography spectrum yields a perfect reflection.
| Cmpd. | absol config | mp°C | [α]25D(deg)(MeOH) | Analgesic ED50 (mg/kg) | rel potency, morphine=1 |
|---|---|---|---|---|---|
| (+)-cis-1a | (βS,3R,4S) | 117–119 | +19.79 | 0.00106 | 13110 |
| (–)-cis-1b | (βR,3R,4S) | 135–137 | -31.91 | 0.0046 | 2990 |
| (–)-trans-1c | (βS,3R,4R) | 107–109 | -0.49 | 0.0097 | 1450 |
| (+)-trans-1d | (βS,3S,4S) | 98–100 | +62.24 | 0.014 | 985 |
| (–)-trans-1e | (βR,3R,4R) | 98–100 | -58.11 | 0.014 | 980 |
| (+)-trans-1f | (βR,3S,4S) | 107–108 | +0.78 | 0.0710 | 196 |
| (+)-cis-1g | (βS,3S,4R) | 135–137 | +33.15 | 10 | |
| (–)-cis-1h | (βR,3S,4R) | 117–119 | -20.54 | >10 |
| Cmpd. | Withdrawal Jumping Culmulative ED50 (mg/kg) | Dependence Potency Index |
|---|---|---|
| (+)-cis-1a | 0.0984 | 92.8 |
| (–)-cis-1b | 0.0007 | 0.15 |
| (–)-trans-1c | 0.0445 | 4.6 |
| (+)-trans-1d | 0.0303 | 2.2 |
| (–)-trans-1e | 0.361 | 5.0 |
| (+)-trans-1f | 0.383 | 5.1 |
| (+)-cis-1g | 60 | 6 |
| (–)-cis-1h | 9.941 | <1 |
- Dependence potency index was obtained by withdrawl jumping cumulative ED50/analgesic ED50.[12]
[edit] OMF2
| Code | Stereochemistry | x Mor |
|---|---|---|
| HC-2ab | (±) | ~4xF |
| 4-MeF | Achiral | ~2xF |
- 4-MeF doesnt have any chiral carbons — it's achiral.
- OMF2 has one chiral carbon — it has two enantiomers.
- Asymmetric synthesis is endorsed inorder to get exclusively the desired isomer.
- QSAR predicts that the (S) enantiomer will be stronger than the (R) enantiomer.
- The enantiopure (S) product is expected to give superior crystal growth to the (±) product,
on the grounds of totally– vs. semi–synthetic methamphetamine.HCl.
[edit] The Most Potent Opioid
1a is 13,000 x stronger than morphine. If a p-F atom is then incorporated into the phenethanol tail, the resultant compound has recently been reported to have a potency of 18K x morphine. p-F-1b was also 4K x stronger than morphine. Hence, upon p-F incorporation, the two most important OMF isomers are both increased in potency by ~1⁄3rd.[13]
Up until the resolution and exploration of the individual isomers of OMF had been accomplished, carfentanil had been popularly interpreted as most potent opioid ever invented (~30 x stronger than fentanyl).[14] This is in fact the same order of potency as OMF unresolved.[15]
- Whereas these totally-synthetic fentanyl analogs show remarkable μ-specificity, some of the high potency semi-synthetic alkaloids nonselective agonists at μ-, δ- and κ-opioid receptors. Dihydroetorphine (DHE ~6K x morphine) and the 14-phenylpropoxy derivatives of various morphinans (e.g. oxymorphone) are illustrative examples of this.title
- More research needs to be done in order to assess if mixed-agonists are a good/bad thing.
- Heroin, for example is likely to be a mixed-agonist. However, kg allotments of opium alkaloids are not readily available.
- Such compounds are in a sense victims of their own success; their extreme potency has meant that they are commonly regarded as too dangerous for human consumption and instead have been applied to veterinary medicine for the immobilization of wild animals.
[edit] Time Release Formulation: Fluorogesic
Professor Q speculates —"there is a good chance that this compound could be made more powerful still, by addition of an α-Me. Although unlikely to increase affinity as such, it would greatly "harden" the agent against metabolic attack, since, as is the case with fentanyl, I would assume N-dealkylation of the piperidine to be the predominant pathway of liver microsomal breakdown. Even if ED50 doesn't go any lower, one would expect duration of action to increase by a factor of three or so...".Opioids.com However, α-Me-OMF is even weaker than trans-3-MeF.[17]
- In view that the propionate salt of testosterone gives it a longer duration of action than the corresponding free alcohol, this analogy might be applicable to RTI-1abcd which also contains a 2° alcohol FG. The rationale for this is that while the propionate reverse ester is reported to be only ≈1⁄5th the potency of OMF, it would gradually hydrolyze to the alcohol in vivo thereby providing a steady and controlled release of OMF into the bloodstream, resulting in the increased duration of analgesia, that is required. Thus it is tentative to presume that 3x the dose could be consumed in the form of the propionate reverse ester which might possibly be effective in the formulation of a time release version of OMF.
In the case of the dopamine reuptake inhibitor vanoxerine and the antipsychotic haloperidol, converting the vacant hydroxyl to decanoate reverse esters yields remarkably long-acting agents with a duration of ~2–4 weeks. It is advised that an ether FG is an preferred embodiment of the invention, due to the fact that it is less susceptible to hydrolysis and is also slightly more lipophilic Et2O vs. EtOAc.
These formulations are representative of so-called prodrugs, but the variety in which an inactive drug is metabolized to an active, not the variety where an already active compound maybe metabolized into another active secondary compound, that possesses radically different pharmacology to the first compound.[18]
- Depot injections must not be taken intravenously, and are suitable only for subcutaneous or intramuscular injection(?)
- A recent patent states that "The present invention provides a stereo-isomer of 3-methyl fentanyl derivative. The pharmacological research shows that it possesses obvious pain-stopping activity, and its action time is long and its addiction is low. Its pain-stopping effect is thousands times that of morphine." However this patent is only available in Chinese.[19]
[edit] Cyclohexanol Agents: Daniel Lednicer & Co.
[edit] Man-Made DOR Agonists
- Some opioid pain–killers were discovered by Daniel Lednicer based on a cyclohexanol framework (1981).[20]
- They have a (delta) δ-amino alcohol.
- One could argue that they are vaguely related to phencyclidine but the validity of this is questionable.
- Delta Opioid Receptor (DOR) agonists are hardcore antidepressants with possible cardiovascular and neuroprotective effex, and powerful convulsion inducing properties, coupled with possible psychomimetic effex(?)[citation needed] These are quite effective.[21]
- The products are achiral, although is a pair of (cis/trans) diastereomers. The trans-diaxial isomer is the more potent of the two.
- The β-Naphthyl has not been used before in this way, although articles on PubMed show that it has worked on similar, yet not identical, (gamma) γ-amino alcohol compounds such as those currently being persued by Paul R. Carlier and Elliott Richelson.[22][23][24][25]
- These are antidepressants that are stronger than Venlafaxine[1990].[26]
- Check this out for how to bake the precursor:[32].
- Notice, how the double Claisen condensation dispenses with the need to implement a H2-bomb (cf. benzo/hydro–quinone).
[edit] Cyclohexanol Fentanyl Analogs
[edit] More on Derivatized Fentanyl Analogs
Carfentanil is one of a long—string of piperidine drugs commercialized by Janssen Pharmaceutica. Its chemical structure is identical to fentanyl, except for the presence of a –CO2Me FG. Carfentanil is ~30 x stronger than fentanyl, and hence a powerful opioid.[28] Although carfentanil's reputation has been bastardized, the common precursor is also relevant to the synthesis of other, pharmaceutically important analogs, such as sufentanil, alfentanil and remifentanil.[29] These are routinely used agents in the arena of surgical anesthesia, but sufentanil is also be used post-operatively as a tranquilizer and is is not just resitricted to theater.[30]
Carfentanil has a high therapeutic index. However in a real-world environment, the dosage is very small, with the effect that those abusing the substance without experience of handling strong pharmaceuticals (particularly opiates) fact a high risk of an overdose. Like most opiates, in the event of overdose, respiratory syndrome can have life-threatening consequences. Even if the victim is successfully resuscitated, they may suffer brain damage resulting from oxygen deprivation.
- 4-HOCH2-F shares the same molecular formula as OMF. Although it is not thought to be favorably bioactive in its own right, it still serves as a platform on which to build more complex analogs,[31] such as the MOM product.
- Insertion of an α-Me into this molecule will increase duration/intensity ~2 x.
- Organometallic addition of XMEt to the the trapped–intermediate of the Strecker amino acid synthesis gives a pharmacophore common to both methadone and ketobemidone. Such SAR overlap is thus likely and might be expected to have a favorable outcome with regards to creating unexplored agents with a longer duration.[citation needed]
Further examples of compounds bearing the same molecular formula OMF can be found on PubMed but will mostly point in the direction of variously substituted benzimidazole type agents.
[edit] References
- ^ [1]J. Med. Chem.; 1995; 38(18); 3652-3659.
- ^ [2] J. Med. Chem.; 1995; 38(9); 1547-1557
- ^ [3] J. Med. Chem.; 1974; 17(10); 1047-1051
- ^ [4] J. Serb. Chem.; 2004; 69(7) 511-526
- ^ [5] J. Med. Chem.; 1962; 5(5); 913-919
- ^ [6] Scienta Sinica Vol. XXIV No. 5 pp 710-721 (May 1981)
- ^ [7]J. Med. Chem.; 1995; 38(18); 3652-3659.
- ^ [8] J. Med. Chem.; 1995; 38(9); 1547-1557
- ^ [9] Scienta Sinica Vol. XXIV No. 5 pp 710-721 (May 1981)
- ^ [10] J. Pharmacol. Exp. Ther. 2000 292: 1127-1134
- ^ [11] Bioorg. Med. Chem. Lett. 10 (2000) 2011-2014
- ^ [12] Life Sciences Volume 67, Issue 2, 2 June 2000, Pages 113-120
- ^ [13] Pharmazie 58: 300-302 (2003)
- ^ [14] J.Serb.Chem.Soc. 67(12)793–802(2002)
- ^ [15] Life Sciences Volume 67, Issue 2 , 2 June 2000, Pages 113-120
- ^ [16] CNS Drug Rev. 2002 Winter;8(4):391-404.
- ^ [17] Scienta Sinica Vol. XXIV No. 5 pp 710-721 (May 1981)
- ^ [18]Journal of Pharmaceutical Sciences Volume 59, Issue 2 , Pages 275 - 275
- ^ [19]Publication number: CN1371903 Publication date: 2002-10-02 Inventor: ZHU YOUCHENG; WU HAO; ZOU YONG.
- ^ [20] J. Med. Chem.; 1981; 24(4); 404-408. (See also some of Daniel Lednicer's books)
- ^ [21] The Antidepressant -like Effects of Delta-Opioid Receptor Agonists Jutkiewicz Mol. Interv..2006; 6: 162-169
- ^ [22]European Journal of Pharmacology Volume 555, Issue 1 , 19 January 2007, Pages 30-36
- ^ [23]United States Patent 6,700,018 Richelson , et al. March 2, 2004
- ^ [24]United States Patent 6,069,177 Carlier, et al. May 30, 2000
- ^ [25] Bioorganic & Medicinal Chemistry Letters Volume 8, Issue 5 , 3 March 1998, Pages 487-492
- ^ [26]J. Med. Chem.; 1990; 33(10); 2899-2905.
- ^ [27]Lednicer United States Patent Search
- ^ [28] J. Serb. Chem.; 2004; 69(11) 843-854
- ^ [29] J.Serb.Chem.Soc. 67(12)793–802(2002)
- ^ [30] Anesth Analg. 2006 Nov;103(5):1311-7
- ^ [31] J. Med. Chem.; 1989; 32(5); 968-974.
[edit] External links
| Analgesics (N02A, N02B) | |
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| Opioids | Bezitramide, Buprenorphine, Butorphanol, Dextromoramide, Dextropropoxyphene, Diamorphine, Dihydrocodeine, Fentanyl, Hydromorphone, Ketobemidone, Methadone, Morphine, Nalbufine, Nicomorphine, Opium, Oxycodone, Papaveretum, Pethidine, Piritramide, Tramadol (see also longer list) |
| Salicylic acid and derivatives | Aspirin (Acetylsalicylic Acid), Diflunisal, Ethenzamide -- See also: NSAIDs |
| Pyrazolones | Aminophenazone, Metamizole, Phenazone |
| Anilides | Paracetamol (acetaminophen), Phenacetin |
| Others | Ziconotide, Tetrahydrocannabinol, Ibuprofen, Ketoprofen, Mefenamic Acid, Naproxen, Diclofenac, Flurbiprofen, Diflunisal, Fenoprofen, Indomethacin, Ketorolac, Meclofenamate, Meloxicam, Piroxicam, Tolmetin |
