MedicinalUser247
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I call this one Bromo-Tripioid. https://ibb.co/NTmdBp2
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N&PD Moderators: Skorpio | someguyontheinternet
Drug designs. (MedicinalUser SAR thread)
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MedicinalUser247
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I call this one Super-Trip. https://ibb.co/2SQZ1p8
MedicinalUser247
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I call this one Super-MDMA. https://ibb.co/379MDfC
Smyth2
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This one reminds me of β-Phenylmethamphetamine.
The precursor for this is 1,1-Diphenylacetone and has dual use in the synthesis of Diphenadione.
α,α-DIPHENYLACETONE
Everett M. Schultz and Sally Mickey
Org. Synth. 1949, 29, 38
DOI: 10.15227/orgsyn.029.0038
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MedicinalUser247
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I call this one Super-Trip-Amide. https://ibb.co/BKg5r83
MedicinalUser247
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I regret to inform you that I will not be posting anymore Drug Designs.
Are you saying
BOUNCE
1-phenyl-1-carbomethoxy-2-methylaminopropane
doesn't work?
Tryptamine and ergoline analogues are not not really my thing.
Maybe next time I get something speedy, I'll try to post your molecules, but some of them seem super hard to name with IUPAC to the point that I'm not sure what you mean.
Try giving the names to me one at a time?
Also, many of them are not correctly named. For example, you can't just say "phenyl etc. etc. 2,3-furan etc. etc. amine" because the 2,3-furan won't come up right in the drawing.
Are you saying
BOUNCE
1-phenyl-1-carbomethoxy-2-methylaminopropane
doesn't work?
Tryptamine and ergoline analogues are not not really my thing.
Maybe next time I get something speedy, I'll try to post your molecules, but some of them seem super hard to name with IUPAC to the point that I'm not sure what you mean.
Try giving the names to me one at a time?
Also, many of them are not correctly named. For example, you can't just say "phenyl etc. etc. 2,3-furan etc. etc. amine" because the 2,3-furan won't come up right in the drawing.
This works in SAR prediction models , but the methyl ester on the beta position will probably reduce the BBB transport..and thus the stimulation.
option is ofcourse to bind the amine to the oxygen...
and create some isomers of the better stims know : oxazolidines.
(pemoline, aminorex , 4- mar)
not a drug , please but a usefull precursor, put extra actyl on the 4-hydroxy.to inhibit dimers .What do you think of this as a drug?
4-HT (4-HydroxyTryptamine)
1-(4-hydroxyindole-3-yl)-2-aminoethane
the Frog returns.
How come?
Surely one needs to present such compounds it as their picrate salt, or failing that at least by something 'energetic' such as a perchlorate?
Isn't it odd that if you ran into such compounds, you would ask for an MSDS. Or, if it turned up, you WOULD carry out some simple studies.
I am reminded of the frankly ridiculous fable spun by 'The Anarchist's Cookbook' in relation to obtaining tetranitromethane...
Welding 4 successive nitrogen atoms is Derek 'tricky' and he is the guy who noted just how many Ns a few ne antibiotics contained.
I checked, and as far as I can tell, the vast majority of novel intermediates have no MSDS date. In short, it's only when something bad happened did people seek to record such things.
Guanidine Ethyl Perchlorate isn't controlled, AFAIK, but I would be fairly certain such a compound was a risk.
Isn't it odd that if you ran into such compounds, you would ask for an MSDS. Or, if it turned up, you WOULD carry out some simple studies.
I am reminded of the frankly ridiculous fable spun by 'The Anarchist's Cookbook' in relation to obtaining tetranitromethane...
Welding 4 successive nitrogen atoms is Derek 'tricky' and he is the guy who noted just how many Ns a few ne antibiotics contained.
I checked, and as far as I can tell, the vast majority of novel intermediates have no MSDS date. In short, it's only when something bad happened did people seek to record such things.
Guanidine Ethyl Perchlorate isn't controlled, AFAIK, but I would be fairly certain such a compound was a risk.
Smyth2
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The tetrazole group is easy you just react the intermediate nitrile with sodium azide.
There are many examples of this in the literature ranging from phenyltropanes to sartan antihypertensives.
Nufenoxole is an interesting synthesis. The azole is reacted with acetic anhydride for the last step.
I know a long list of compounds with 4 consecutive nitrogens. If you've read Danny's books, i'm sure you know that Molinazone is the one that is mentioned there.
There are many examples of this in the literature ranging from phenyltropanes to sartan antihypertensives.
Nufenoxole is an interesting synthesis. The azole is reacted with acetic anhydride for the last step.
I know a long list of compounds with 4 consecutive nitrogens. If you've read Danny's books, i'm sure you know that Molinazone is the one that is mentioned there.
Oh, tetrazoles do turn up in medicinal chemistry on occasion. But in a roundabout way I was pointing out that quite often, medicinal chemists don't appreciate the energetic nature of such rings.
Or hazards more generally.
Smyth2
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I think I have stumbled on a completely ingenious new idea.
Cross between Liming Shao (Sepracor/Sunovion) and Stacey Lomenzo (New Orleans) to arrive at SNDRI with opioid pharmacology:
The only original suggestion that I have made that is not based on the previous authors was to use a phenethyl group instead of the Me-N to potentiate the activity for the mu-receptor.
Reading List:
[1] Liming Shao, 11 More », WO2007081857 (2007 to Sepracor Inc.).
[2] Shao, Liming; Hewitt, Michael C.; Wang, Fengjiang; Malcolm, Scott C.; Ma, Jianguo; Campbell, John E.; Campbell, Una C.; Engel, Sharon R.; Spicer, Nancy A.; Hardy, Larry W.; Schreiber, Rudy; Spear, Kerry L.; Varney, Mark A. (2011). "Discovery of N-methyl-1-(1-phenylcyclohexyl) methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor". Bioorganic & Medicinal Chemistry Letters. 21 (5): 1438–1441. doi:10.1016/j.bmcl.2011.01.016.
[3] Shao, Liming; Hewitt, Michael C.; Wang, Fengjiang; Malcolm, Scott C.; Ma, Jianguo; Campbell, John E.; Campbell, Una C.; Engel, Sharon R.; Spicer, Nancy A.; Hardy, Larry W.; Schreiber, Rudy; Spear, Kerry L.; Varney, Mark A. (2011). "Discovery of N-methyl-1-(1-phenylcyclohexyl) ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor". Bioorganic & Medicinal Chemistry Letters. 21 (5): 1434–1437. doi:10.1016/j.bmcl.2011.01.019.
[4] Lomenzo SA, Izenwasser S, Gerdes RM, Katz JL, Kopajtic T, Trudell ML. Synthesis, dopamine and serotonin transporter binding affinities of novel analogues of meperidine. Bioorg Med Chem Lett. 1999 Dec 6;9(23):3273-6. doi: 10.1016/s0960-894x(99)00606-x. PMID: 10612583.
[5] Lomenzo SA, Rhoden JB, Izenwasser S, Wade D, Kopajtic T, Katz JL, Trudell ML. Synthesis and biological evaluation of meperidine analogues at monoamine transporters. J Med Chem. 2005 Mar 10;48(5):1336-43. doi: 10.1021/jm0401614. PMID: 15743177.
[6] Rhoden JB, Bouvet M, Izenwasser S, Wade D, Lomenzo SA, Trudell ML. Structure-activity studies of 3'-4'-dichloro-meperidine analogues at dopamine and serotonin transporters. Bioorg Med Chem. 2005 Oct 1;13(19):5623-34. doi: 10.1016/j.bmc.2005.05.025. PMID: 15993612.
[7] Gu X, Izenwasser S, Wade D, Housman A, Gulasey G, Rhoden JB, Savoie CD, Mobley DL, Lomenzo SA, Trudell ML. Synthesis and structure-activity studies of benzyl ester meperidine and normeperidine derivatives as selective serotonin transporter ligands. Bioorg Med Chem. 2010 Dec 1;18(23):8356-64. doi: 10.1016/j.bmc.2010.09.060. Epub 2010 Sep 29. PMID: 20980153; PMCID: PMC3713777.
Cross between Liming Shao (Sepracor/Sunovion) and Stacey Lomenzo (New Orleans) to arrive at SNDRI with opioid pharmacology:
The only original suggestion that I have made that is not based on the previous authors was to use a phenethyl group instead of the Me-N to potentiate the activity for the mu-receptor.
Reading List:
[1] Liming Shao, 11 More », WO2007081857 (2007 to Sepracor Inc.).
[2] Shao, Liming; Hewitt, Michael C.; Wang, Fengjiang; Malcolm, Scott C.; Ma, Jianguo; Campbell, John E.; Campbell, Una C.; Engel, Sharon R.; Spicer, Nancy A.; Hardy, Larry W.; Schreiber, Rudy; Spear, Kerry L.; Varney, Mark A. (2011). "Discovery of N-methyl-1-(1-phenylcyclohexyl) methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor". Bioorganic & Medicinal Chemistry Letters. 21 (5): 1438–1441. doi:10.1016/j.bmcl.2011.01.016.
[3] Shao, Liming; Hewitt, Michael C.; Wang, Fengjiang; Malcolm, Scott C.; Ma, Jianguo; Campbell, John E.; Campbell, Una C.; Engel, Sharon R.; Spicer, Nancy A.; Hardy, Larry W.; Schreiber, Rudy; Spear, Kerry L.; Varney, Mark A. (2011). "Discovery of N-methyl-1-(1-phenylcyclohexyl) ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor". Bioorganic & Medicinal Chemistry Letters. 21 (5): 1434–1437. doi:10.1016/j.bmcl.2011.01.019.
[4] Lomenzo SA, Izenwasser S, Gerdes RM, Katz JL, Kopajtic T, Trudell ML. Synthesis, dopamine and serotonin transporter binding affinities of novel analogues of meperidine. Bioorg Med Chem Lett. 1999 Dec 6;9(23):3273-6. doi: 10.1016/s0960-894x(99)00606-x. PMID: 10612583.
[5] Lomenzo SA, Rhoden JB, Izenwasser S, Wade D, Kopajtic T, Katz JL, Trudell ML. Synthesis and biological evaluation of meperidine analogues at monoamine transporters. J Med Chem. 2005 Mar 10;48(5):1336-43. doi: 10.1021/jm0401614. PMID: 15743177.
[6] Rhoden JB, Bouvet M, Izenwasser S, Wade D, Lomenzo SA, Trudell ML. Structure-activity studies of 3'-4'-dichloro-meperidine analogues at dopamine and serotonin transporters. Bioorg Med Chem. 2005 Oct 1;13(19):5623-34. doi: 10.1016/j.bmc.2005.05.025. PMID: 15993612.
[7] Gu X, Izenwasser S, Wade D, Housman A, Gulasey G, Rhoden JB, Savoie CD, Mobley DL, Lomenzo SA, Trudell ML. Synthesis and structure-activity studies of benzyl ester meperidine and normeperidine derivatives as selective serotonin transporter ligands. Bioorg Med Chem. 2010 Dec 1;18(23):8356-64. doi: 10.1016/j.bmc.2010.09.060. Epub 2010 Sep 29. PMID: 20980153; PMCID: PMC3713777.
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Smyth2
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I checked my database and forgot to acknowledge that Pheneridine is only 2x meperidine and not like fentanyl or PEPAP potentiation.
Out of the side-chains tested, cinnamyl was highest albeit still only 29 x meperidine.
Elpern, Bill; Gardner, Lorraine N.; Grumbach, Leonard (1957). "Strong Analgesics. The Preparation of Some Ethyl 1-Aralkyl-4-phenylpiperidine-4-carboxylates1". Journal of the American Chemical Society. 79 (8): 1951–1954. doi:10.1021/ja01565a050.
N-Me has never been made so this is still an interesting place to start.
The ultimate compound would be to also include the alpha-methyl on the phenethyl side-chain; however, this would involve the use of amphetamine as a precursor and is therefore not a good place to start.
Out of the side-chains tested, cinnamyl was highest albeit still only 29 x meperidine.
Elpern, Bill; Gardner, Lorraine N.; Grumbach, Leonard (1957). "Strong Analgesics. The Preparation of Some Ethyl 1-Aralkyl-4-phenylpiperidine-4-carboxylates1". Journal of the American Chemical Society. 79 (8): 1951–1954. doi:10.1021/ja01565a050.
N-Me has never been made so this is still an interesting place to start.
The ultimate compound would be to also include the alpha-methyl on the phenethyl side-chain; however, this would involve the use of amphetamine as a precursor and is therefore not a good place to start.
Smyth2
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i checked my database and realized that this compound is the most similar to my idea:
pubchem.ncbi.nlm.nih.gov
The pharmacology is only listed as NK1/SSRI whereas my idea was a SNDRI/opioid.
[1] Millan, Mark J. (2009). "Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs". Neurotherapeutics. 6 (1): 53–77. doi:10.1016/j.nurt.2008.10.039.
[2] Peter Bernstein, et al. WO2004020411 (AstraZeneca AB).
3-cyano-N-[[4-(3,4-dichlorophenyl)-1-methylpiperidin-4-yl]methyl]-N-methylnaphthalene-1-carboxamide
3-cyano-N-[[4-(3,4-dichlorophenyl)-1-methylpiperidin-4-yl]methyl]-N-methylnaphthalene-1-carboxamide | C26H25Cl2N3O | CID 9934231 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information...
pubchem.ncbi.nlm.nih.gov
[1] Millan, Mark J. (2009). "Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs". Neurotherapeutics. 6 (1): 53–77. doi:10.1016/j.nurt.2008.10.039.
[2] Peter Bernstein, et al. WO2004020411 (AstraZeneca AB).
Pheneridine looks awfully similar to phenoperidine - the potent opioid used for surgery before fentanyl was developed.
Phenoperidine is listed as anywhere between x20 and x80 M in potency. Janssen actually wrote a paper on the various N-substituted derivatives of pethidine and MPPP (for want of a proper name). As the chain gets longer (N-propyl being optimal), the difference in the ester function appears to matter much less.
The hydroxy is chiral and QSAR analysis shows that be it on a ethyl or propyl chain, it increases activity if it's on the benzylic carbon. Other classes with an N-phenylethyl also exhibit this pattern which for the sake of 3DQSAR might just be thought of as a HBA (hydrogen bond acceptor) since other HBAs also increase activity.
Phenoperidine is listed as anywhere between x20 and x80 M in potency. Janssen actually wrote a paper on the various N-substituted derivatives of pethidine and MPPP (for want of a proper name). As the chain gets longer (N-propyl being optimal), the difference in the ester function appears to matter much less.
The hydroxy is chiral and QSAR analysis shows that be it on a ethyl or propyl chain, it increases activity if it's on the benzylic carbon. Other classes with an N-phenylethyl also exhibit this pattern which for the sake of 3DQSAR might just be thought of as a HBA (hydrogen bond acceptor) since other HBAs also increase activity.