Just today a friend, an Afghan HR worker was nearly killed in a bombing in Kabul. On one hand The Taliban (enemy of the US) are the Mujahideen (supported by the US) and in both cases, heroin pays for the weapons - so don't forget that the US government cares more about proxy wars than organized crime (The Taliban ARE a form of organized crime). The world has now been blighted by ever more dubious fentanyl analogues with so many companies in China & India supplying these technically legal poisons. Cayman Chemicals is a HUGE supplier and my only thought on this is that I know, so does the DEA. Just why they carry on unmolested I don't know but I'm sure many theories exist. One might be that 3-F fentanyl isn't covered by the UK MoDA and I suspect continually changing novel agents doesn't give a window to launch a large legal action.
The question is, are all opioids equally dangerous? We have the figures:
TI (LD50/ED50)
Methadone - 12
Meperidine - 28
Morphine - 76
Fentanyl - 300
Sufentanil - 25000
Professor Helmut Schmidhammer carried out QSAR studies on a whole host of phenanththracine derivatives with truly huge TIs. In fact, several examples show a ceiling to the respiratory depression. In addition, BIMU8 has been shown to reverse the respiratory depression caused by etorphine and carfentanil but even without that, we truly can produce opioids with an ED50 around that of etorphine and the LD50 around that of codeine. Imagine - you could eyeball something and while yes, you will pass out (with the attendant risks) but you won't stop breathing or inhale vomit and turn blue.
About 6 years ago I ran a large training set that included allylprodine, 14-cinnamyloxycodeinone, Sufentanil, 14-MeO metopon, 14-phenylpropoxymetopon, the etonitazene derivative ((2S)-2-(4-methoxyphenyl)-2-{1-[2-(diethylamino)ethyl]-5-nitro-1H-benzimidazol-2-yl}ethanamide), (1S,4R)-4-dimethylamino-4-(4-bromophenyl)-1-[2-(furan-2-yl)ethyl]-3,3-dimethylcyclohexanol (BDPC derivative), Ro4-1539, etorphine, 8-Carboxamidocyclazocine (and the substituted amides listed in the work of Mark P. Wentland), 1-[1-(furan-2-ylmethyl)-4-(3-hydroxyphenyl)piperidin-4-yl]propan-1-one (with 3-(1,3-dimethyl-4-propylpiperidin-4-yl)phenol - ring-substitution of ketobemidone yields an agonist & antagonist isomtric pair which is why no papers list the potent derivatives), N-[(2R)-1-(3,3-dimethylpiperidin-1-yl)propan-2-yl]-N-phenylacetamide (overlays α,3-dimethyl fentanyl. If you were going to put a 3, put a 3,3 for x2 activity), Tlidine, 1-{1-[(1S)-1-(furan-2-yl)ethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, N-(3,3-diphenyl-4-oxohex-1-yl)-7,8-benzo-3-azaspiro[5.5]undecane
and padded it out with a large series of potent but quite unknown compounds (see Opiates by R. Lenz et al). All of the above is in the work of Lenz and/or other references provided.
Here are some useful links so you may check my work and correct and improve it:
https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1958-01-01_4_page007.html
http://www.pnas.org/content/pnas/73/11/4215.full.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2137165/
https://encrypted.google.com/patents/DE60026883T2?cl=de (look at references cited)
https://patents.google.com/patent/US3464994
Prepn: Ziering et al., J. Org. Chem. 22, 1521 (1957); Lee, Ziering, US 2798073 (1957 to Hoffmann-La Roche)
US4960788 (Pyrrolidone-2 compounds and their use for central analgesic activity)
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 Volume 48, Issue 23, 1991, Pages PL111-PL116)
Anybody who would take the time to download CHARMM (J Mol Model (2011) 17:477–493 gives details on how to apply 3D QSAR to the named compounds) can do the same as me.
But my own 'I like to draw random molecules) isn't random and is provided in SMILES for easy import (and preventing idiots copying and using the structure).
O[C@H](CN3CC[C@@]24CCCC[C@@]4(OC)[C@H]3Cc1ccc(O)cc12)c5ccco5
So, why the above? Well μ2/κ3/δ agonism (with sub-nm affinity) provide huge potency but more importantly, the agent is a δ partial agonist and a κ1/κ2 antagonist so respiratory depression is vastly reduced. If you look at the UNODC link and the references you will see that Janssen produced a series of lengthy papers on different classes of opioids with the ED50 & LD50 being amongst the most prominent pieces of data. Would anyone be surprised that the LD50 of Ro4-1539 is actually slightly HIGHER than levorphanol (increase MW)? So that's a x60 increase in the TI right there. I'm sure everyone has taken a good look at the metopon data and already know of the circa 2500 TI. This isn't some secret. This is research from world class teams with huge amounts of experience and papers with tremendous impact factors.
Can I state on pain of death that the material is benign? Well, I would be willing to IV 10mg of it and considering it's about x3400 morphine, by rights that should kill me outright but I'm prepared to take what I consider a pretty low risk test.
The next, obvious point is 'how the hell can that be made! Reaxys lists 11 steps! It's pie in the sky, idiot, nobody CAN make it!'
Not so. A combinational route from legal, commercially available precursors is a total of 6 steps. Not 1->2->3->4->5->6 because that would still be crazy. 1->2->3 & 4->5->6 ===> 3+6->7->8 i.e. 3 x 2 steps. We don't discuss synthesis on this site for a host of very good reasons. I think I can reasonably state that the key step is dequaternization of an amine using sodium thiophenolate.
Have I sampled this one? No. Have I sampled some of the novel high-potency ones? Yes. Back when it was all 100% legal in the UK. I don't break the law. That is my thing. I don't thrill at outsmarting the police and security services. I just don't break the law and that really, really does piss them off. Have I made bad decisions? Yes. Just 1 but people were harmed and I had a nervous breakdown. 1 person harmed is 1 to many for me so I have I hope been honest and even-handed while echoing the words of Dr. Dave 'BE CAREFUL'.
The question is, are all opioids equally dangerous? We have the figures:
TI (LD50/ED50)
Methadone - 12
Meperidine - 28
Morphine - 76
Fentanyl - 300
Sufentanil - 25000
Professor Helmut Schmidhammer carried out QSAR studies on a whole host of phenanththracine derivatives with truly huge TIs. In fact, several examples show a ceiling to the respiratory depression. In addition, BIMU8 has been shown to reverse the respiratory depression caused by etorphine and carfentanil but even without that, we truly can produce opioids with an ED50 around that of etorphine and the LD50 around that of codeine. Imagine - you could eyeball something and while yes, you will pass out (with the attendant risks) but you won't stop breathing or inhale vomit and turn blue.
About 6 years ago I ran a large training set that included allylprodine, 14-cinnamyloxycodeinone, Sufentanil, 14-MeO metopon, 14-phenylpropoxymetopon, the etonitazene derivative ((2S)-2-(4-methoxyphenyl)-2-{1-[2-(diethylamino)ethyl]-5-nitro-1H-benzimidazol-2-yl}ethanamide), (1S,4R)-4-dimethylamino-4-(4-bromophenyl)-1-[2-(furan-2-yl)ethyl]-3,3-dimethylcyclohexanol (BDPC derivative), Ro4-1539, etorphine, 8-Carboxamidocyclazocine (and the substituted amides listed in the work of Mark P. Wentland), 1-[1-(furan-2-ylmethyl)-4-(3-hydroxyphenyl)piperidin-4-yl]propan-1-one (with 3-(1,3-dimethyl-4-propylpiperidin-4-yl)phenol - ring-substitution of ketobemidone yields an agonist & antagonist isomtric pair which is why no papers list the potent derivatives), N-[(2R)-1-(3,3-dimethylpiperidin-1-yl)propan-2-yl]-N-phenylacetamide (overlays α,3-dimethyl fentanyl. If you were going to put a 3, put a 3,3 for x2 activity), Tlidine, 1-{1-[(1S)-1-(furan-2-yl)ethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, N-(3,3-diphenyl-4-oxohex-1-yl)-7,8-benzo-3-azaspiro[5.5]undecane
and padded it out with a large series of potent but quite unknown compounds (see Opiates by R. Lenz et al). All of the above is in the work of Lenz and/or other references provided.
Here are some useful links so you may check my work and correct and improve it:
https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1958-01-01_4_page007.html
http://www.pnas.org/content/pnas/73/11/4215.full.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2137165/
https://encrypted.google.com/patents/DE60026883T2?cl=de (look at references cited)
https://patents.google.com/patent/US3464994
Prepn: Ziering et al., J. Org. Chem. 22, 1521 (1957); Lee, Ziering, US 2798073 (1957 to Hoffmann-La Roche)
US4960788 (Pyrrolidone-2 compounds and their use for central analgesic activity)
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 Volume 48, Issue 23, 1991, Pages PL111-PL116)
Anybody who would take the time to download CHARMM (J Mol Model (2011) 17:477–493 gives details on how to apply 3D QSAR to the named compounds) can do the same as me.
But my own 'I like to draw random molecules) isn't random and is provided in SMILES for easy import (and preventing idiots copying and using the structure).
O[C@H](CN3CC[C@@]24CCCC[C@@]4(OC)[C@H]3Cc1ccc(O)cc12)c5ccco5
So, why the above? Well μ2/κ3/δ agonism (with sub-nm affinity) provide huge potency but more importantly, the agent is a δ partial agonist and a κ1/κ2 antagonist so respiratory depression is vastly reduced. If you look at the UNODC link and the references you will see that Janssen produced a series of lengthy papers on different classes of opioids with the ED50 & LD50 being amongst the most prominent pieces of data. Would anyone be surprised that the LD50 of Ro4-1539 is actually slightly HIGHER than levorphanol (increase MW)? So that's a x60 increase in the TI right there. I'm sure everyone has taken a good look at the metopon data and already know of the circa 2500 TI. This isn't some secret. This is research from world class teams with huge amounts of experience and papers with tremendous impact factors.
Can I state on pain of death that the material is benign? Well, I would be willing to IV 10mg of it and considering it's about x3400 morphine, by rights that should kill me outright but I'm prepared to take what I consider a pretty low risk test.
The next, obvious point is 'how the hell can that be made! Reaxys lists 11 steps! It's pie in the sky, idiot, nobody CAN make it!'
Not so. A combinational route from legal, commercially available precursors is a total of 6 steps. Not 1->2->3->4->5->6 because that would still be crazy. 1->2->3 & 4->5->6 ===> 3+6->7->8 i.e. 3 x 2 steps. We don't discuss synthesis on this site for a host of very good reasons. I think I can reasonably state that the key step is dequaternization of an amine using sodium thiophenolate.
Have I sampled this one? No. Have I sampled some of the novel high-potency ones? Yes. Back when it was all 100% legal in the UK. I don't break the law. That is my thing. I don't thrill at outsmarting the police and security services. I just don't break the law and that really, really does piss them off. Have I made bad decisions? Yes. Just 1 but people were harmed and I had a nervous breakdown. 1 person harmed is 1 to many for me so I have I hope been honest and even-handed while echoing the words of Dr. Dave 'BE CAREFUL'.
Last edited: