Author Topic: J Med Chem Paper with DOB-like phenethylamines  (Read 4645 times)

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Acme

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J Med Chem Paper with DOB-like phenethylamines
« on: October 24, 2001, 06:01:00 AM »
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

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Re: J Med Chem Paper with DOB-like phethylamines
« Reply #1 on: October 24, 2001, 07:59:00 AM »
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

  • Guest
Re: J Med Chem Paper with DOB-like phethylamines
« Reply #2 on: October 24, 2001, 08:52:00 AM »
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

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #3 on: October 24, 2001, 11:20:00 AM »
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

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Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #4 on: October 24, 2001, 12:42:00 PM »
How do you make the Cyano or Isocyano from the halogenated PEA?

yellium

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Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #5 on: October 24, 2001, 01:45:00 PM »

Post 108811

(dormouse: "Thiocyanation of 2C-H  -Rhodium", Novel Discourse)

Rhodium

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #6 on: October 24, 2001, 07:22:00 PM »
That is a procedure for the thiocyanate - that shouldn't work with cyanide... And besides, the procedure does not start with the halo PEA.

megamole

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Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #7 on: October 24, 2001, 08:08:00 PM »
The cyano compound could be made by preparing the 4-carboxylic PEA, then converting it to the nitrile in the last step. the carboxylate could be prepared by coverting 4-bromo-2,5-dimethoxybenzaldehyde to its corresponding dioxolane, then treating with magnesium to form the Grignard reeagent. The grignard intermediate is then treated with dry ice, and there you have it.

Rhodium

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #8 on: October 24, 2001, 10:01:00 PM »
I think I'd rather do a sandmeyer on a 4-amino-PEA. I have found quite a few references on such reactions where the aliphatic amine is left untouched.

BTW, can you do a sandmeyer with copper(I)azide, or will it explode?

hest

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #9 on: October 24, 2001, 11:05:00 PM »
I't might work, but Cu.azide is much less stabel than lead azide :-[

slappy

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #10 on: October 25, 2001, 03:27:00 AM »
No no no...

4-Halo-PEA with Zn(CN)2 or CuCN, in DMF or Dimethylacetamide catalysed by a Pd(0) Complex. Like Pd(PPh3)4, although other ligand complexes give better conversion. High yields (>90%) when the ring is sufficiently activated.

As usual, references available on request. ;)

Acme

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #11 on: October 25, 2001, 04:01:00 AM »
Acid to ester (drop sulf in MeOH), ester to carboxamide (liq NH3, sealed tube  8)  or aq NH3 reflux), POCl3 reflux strip, very quantitative

maybee Boc or Z here
then you can do a Pinner reaction thereafter 1 eq EtOH, HCl(g) bnezene/DCM
to get the amino imidate salt,
then amidine, cyclic or not or aminooxime in EtOH or AcOH maybee

or tertrazole with Na azide hell might even be able to do that directly from free amine cyano compound

Maybee the oxadiazole too from the Ester

whatever you would want to
but what would you want to do?
of that which remains to be done
this compound 2 from the paper I mentioned
with 2 nM
is a n-propyl-3-phenyl

yellium

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #12 on: October 25, 2001, 10:42:00 AM »
BTW: I wouldn't be surprised if gamma-2C-T-4 and gamma-DOM
are 5ht2-antagonists too. Would explain why they're `weird' compounds.

Rhodium

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #13 on: October 25, 2001, 11:40:00 AM »
Slappy: Refs for that Cyano/Pd reaction, please!

Yellium: What do you mean by "gamma-DOM"?

yellium

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #14 on: October 25, 2001, 06:47:00 PM »
PiHKAL #69. Compare also TMA-6, which also has no 2,5-substitution pattern.


Rhodium

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #15 on: October 25, 2001, 11:43:00 PM »
That's not gamma, it's Psi (Pseudo).

slappy

  • Guest
Pd-catalyzed Cyanation of Aryl Halides
« Reply #16 on: October 25, 2001, 11:49:00 PM »
All of these routes are very similar. All using either the Aryl Bromide or Chloride. Zn(CN)2 as the CN donor. Catalytic amounts of the Pd(0) complex, like Pd2(dba)3[tris(dibenzylideneacetone)dipalladium] which gives the best results, or Pd(PPh3)4 and dppf [1,10-bis(diphenylphosphino)ferrocene], which is commonly used as a ligand to enhance the reactivity of a palladium complex, in a polar aprotic solvent like MeCN, N,N-Dimethylformamide(DMF), N,N-Dimethylacetamide(DMA), 1-Methyl-2-Pyrrolidinone(NMP) are all suitable solvents. Although wet DMF seemes to give the best results. Mild heat (<150°C) and agitation.

Tetrahedron Lett. 40 (1999) 8193-8195
       - Aryl Bromide, Zn(CN)2 and a variety of Palladiu-Phosphine ligand complexes
Tetrahedron Lett. 41 (2000) 3271-3273
       - Aryl Chloride, Zn(CN)2, and catalytic amounts of Pd2(dba)3, dppf, and Zn(dust) in DMA. >90% yields.
Synth.Commun. 24,6 (1994) 887-890
       - ArX + Zn(CN)2+ Pd(PPh3)4, in DMF, 6h @ 80°C
Collect.Czech.Chem.Commun. 48,6 (1983) 1765-1773
       - Similar to above, but using Crown Ethers
Can.J.Chem. 63 (1985) 111-120
       - ArX, CuCN, Pd(0) in DMA
J.Org.Chem. 51,24 (1986) 4714-4716
       - ArX, Et3, Pd(PPh3)4

yellium

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #17 on: October 26, 2001, 04:03:00 PM »
I took it from the online version of pihkal (@erowid). Shulgin himself is also not really clear about gamma and psi  :P .

From the TMA-6 entry:

[...] And the first indicators are that, in keeping the 2,6-dimethoxy aspect intact, a completely analogous series could be made, again with modifications of the 4-position. These have been named the psu-series, or psi-series, as an abbreviation for the prefix, pseudo,
and can be differentiated from the 2,4,5-things with the use of the Greek letter "gamma". Thus there is the gamma-DOM (called Z-7 in this book, and certainly an active compound), and gamma-DOB, gamma-DOET, gamma-DOI, and the gamma-ALEPH compounds. And, of course, the gamma-2C-X counterparts. I would expect all of them to be active and, certainly, some of them interesting. They will be considerably more difficult to synthesize. However, some of them, specifically things such as gamma-2C-T-4, have already been prepared, and are being evaluated.





Rhodium

  • Guest
Re: J Med Chem Paper with DOB-like phenethylamine
« Reply #18 on: October 26, 2001, 04:25:00 PM »
There is the source of confusion. In the real book, the letter Psi is represented, but they have translated it wrong to "gamma" in the online version. Could somebody ask erowid to change that?

megamole

  • Guest
4-cyano-2,5-dimethoxy-PEA (2C-CN) and DOCN
« Reply #19 on: October 26, 2001, 06:18:00 PM »
Just for the record, 4-cyano-2,5-dimethoxy-PEA and its corresponding amphetamine have been synthesized. The experimental details can be found in

J. Med. Chem. 27(4), 513-520 (1984)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/2c-c.2c-cn.synthesis.pdf)