Ohmefentanyl
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Ohmefentanyl
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| Systematic (IUPAC) name | |
| cis-N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidinyl]-N-phenylpropanamide | |
| Identifiers | |
| CAS number | 78995-14-9 |
| ATC code | ? |
| PubChem | 199550 |
| Chemical data | |
| Formula | C23H30N2O2 |
| Mol. weight | 366.5022 |
| Physical data | |
| Melt. point | 117-119 135-137 °C (Expression error: Unexpected number °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 |
Contents |
[edit] Introduction
Ohmefentanyl (OMF) is related to a fentanyl analogue called 3-methyl-fentanyl (3-MF)[1],[2]. OMF is more sophisticated than 3-MF though since it also has a β-hydroxy group situated on the phenethyl tail.
The primary effect of the 3-methyl and β-hydroxy group are to amplify the potency of fentanyl.
OMF has 3 chiral carbons and subsequently there are 8 possible isomers of this compound. The synthesis and preliminary evaluation of the individual isomers of OMF was reported independently by Chinese [3] and American scientists [4] in 1995.
[edit] Stereochemistry
In general only the cis isomers of OMF are considered as having any real importance, the trans isomers are not usually desired due to their lower activity. For example, according to Serbian research, syn-3-MF is 6 x fentanyl, whereas trans-3-MF is equipotent to fentanyl. Furthermore, the (+)-isomer of syn-3-MF is reported as being some 19 x stronger than fentanyl.
The potency of OMF follows a similar pattern to that seen for 3-MF. Hence for the syn isomers, although there are two possible configurations of groups about the piperidine ring [(3S,4R) and (3R,4S)], the potency of the resultant compound derives from only one of these available configurations (3R,4S).
Moreover, in addition to the stereochemistry about the piperidine ring, there is also the added complexity of having to consider that there are two possible enantiomers for the hydroxyl group since it is also attached to a chiral carbon atom.
The isomer having the (3R,4S,βS) configuration (F9204) has a potency of 13,000 x morphine whereas the compound with (3R,4S,βR) stereochemistry (F9202) has a potency of 3000 x morphine according to work published by the Chinese. The combined potency of these two isomers, ie. the racemate w.r.t. the alcohol, is reported to be 6300 x morphine. Work done on the behavioral pharmacology of this pair of isomers has yielded some interesting findings [5]. For example, 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 addition is low. Its pain-stopping effect is thousands times that of morphine."[6]
The codename RTI-4614-4 has been applied to the four syn isomers of 3-Me-β-OH-fentanyl. Although the potency of this compound is conferred by and large by the (3R,4S) isomers, the other two isomers having (3S,4R) stereochemistry about the piperidine ring are also worthy of consideration.
Compounds with superstrength analgesia thousands of times superior to morphine cause pseudo-irreversible down regulation of opioid receptors. This leads to rapid tolerance and dependence. Eventually if the opioid receptors on the GPCR get pulled far enough into the wall of the endoplasmic reticulum, biomolecules known as arrestins consume these cells. This results in a decreased density of these cells across the receptor surface. The relevance of this is that the two isomers of RTI-4614-4 having (3S,4R) stereochemistry can serve to decrease the likelihood of this occurring [7].
[edit] Most Potent Opioid
The most potent isomer of OMF (3R,4S,βS) is already 13,000 times stronger than morphine. If a p-fluoro atom is then incorporated into the phenethanol tail end of the molecule, the resultant compound has recently been reported to have a potency of 18,000 x morphine [8]. If this finding is correct, this compound would be the most potent opioid ever discovered. Until recently, carfentanil was believed to be the most potent opioid ever invented having a strength reported as being 100 times greater than fentanyl. On a side note, the (3R,4S,βR) isomer of p-fluoro-OMF was 4000 x stronger than morphine. Thus both of the active isomers in OMF are increased in potency by roughly 1/3rd upon incorporation of a p-fluoro atom.
[edit] Misconceptions
It is said that "there is a good chance that this compound could be made more powerful still, by addition of an alpha-methyl substituent. 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...." [9]. However according to an article produced by Chinese scientists a considerable time ago, the β-hydroxy does not mix well with an α-methyl [10]. This effect is so pronounced that α-methyl-OMF is weaker than fentanyl.
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-4614-4 which also contains a 2° alcohol moiety.
The rationale for this is that while the propionate reverse ester might only be 1/5th the potency of OMF in its own right, it would gradually break-down 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 a higher dose of OMF could be consumed in the form of the propionate reverse ester which might possibly be effective in the formulation of a time release vesion of OMF. Working examples of this concept is for the DAT inhibitor vanoxerine and the decanoate ester of haloperidol.
Such depot formulations are unsuitable for IV injection and most be administered intramuscularly.
[edit] References
- ^ J. Med. Chem.; 1974; 17(10); 1047-1051
- ^ J. Serb. Chem.; 2004; 69(7) 511-526
- ^ J. Med. Chem.; 1995; 38(18); 3652-3659
- ^ J. Med. Chem.; 1995; 38(9); 1547-1557
- ^ Life Sciences Volume 67, Issue 2 , 2 June 2000, Pages 113-120
- ^ CN1371903
- ^ J. Pharmacol. Exp. Ther. 2000 292: 1127-1134
- ^ Pharmazie 58: 300-302 (2003)
- ^ Pharmazie 58: 300-302 (2003)
- ^ Scienta Sinica Vol. XXIV No. 5 pp 710-721 (1979)
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