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J Med Chem Paper with DOB-like phenethylamines

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Acme:
J Med Chem 2001, 44, 3283-3291

Compound 6 looks very accessible

and with a Ki of 13 nM in an 5-HT2A

where DOB is 32 nM.

They also mention compound 2, whose work is in press, that is 8nM.

And what the hell are these sarpogrelate and SR46349B chemical entities all about?

Quicksilver:
In response to:
Poster: Acme
Subject: J Med Chem Paper with DOB-like phethylamines
[snip] And what the hell are these sarpogrelate and SR46349B chemical entities all about?

They are 5HT antagonists at the receptor level.  (as opposed to the reuptake level)

Acme:
antagonism at the receptor level sounds like a bummer


but do they have any interesting properties or uses is more the question, i've never heard of them.

slappy:
Okay, so here's the deal (as I know it):

They found that the 2,5-Dimethoxy substituent pattern was not required for high receptor binding affinity in 5HT2A ligands, but the catch being that they exibit antagonistic character. Sarpogrelate and SR46349B are just standard 5-HT2 antagonists that these novel antagonists are being compared to. Like how novel 5-HT1A,2A&2C agonists are compared to DOI, LSD, or LY293284.

Out of the Phenylisopropylamines, the DOB and DOTFM analouges with the Benzodifuran1,2, and Tetrahydrobenzodifuran3 moieties seem to be the most potent agonists (=fun).

I still find DOTFM interesting, as it is easily accessable through DOI or DOB, although still being about equipotent. It's effects in humans is still largely unknown, unless you are inclined to believe Drone's rumors in Post 122784 (dormouse: "Bromo-benzodifuranyl-isopropylamine  -Lilienthal", Serious Chemistry). I know that humans are virtually unable to metabolize Trifluoromethyl groups, apperently it just won't leave the receptor? Its ridiculously electronegative, And still very hydrophobic -- it CAN'T hydrogen bond to anything. No enzyme can bind to it. As Dr. Shulgin put it "its the world's shortest length of teflon", and essentially that is what it is. (To borrow a few word's from Drone)

On a similar note, does anyone know why the 4-Cyano or Isocyano compounds have not been explored? These are also easily accessable from the aromatic halogens. I remember Assholium talked of 2-C 4-thiocyanate, and gave conformation that it was indeed active (and fun!). ;D

References

1) J. Med. Chem. 44, 2001, 1003-1010 (https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols-dragonfly-2.pdf)
2) J. Med. Chem. 41, 1998, 5148-5149 (https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols-dragonfly-1.pdf)
3) J. Med. Chem. 39, 1996, 2953-2961 (https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols-dihydrobenzofuran-3-fly.pdf)

All by the Nichols group of course. ;)

Rhodium:
How do you make the Cyano or Isocyano from the halogenated PEA?

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