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Nichols: Novel Naphtofuran 5-HT2A ligands
Rhodium:
Synthesis and Pharmacological Characterization of a Series of Geometrically Constrained 5-HT2A/2C Receptor Ligands
James J. Chambers, Jason C. Parrish, Niels H. Jensen, Deborah M. Kurrasch-Orbaugh, Danuta Marona-Lewicka, and David E. Nichols
J. Med. Chem. 46 (16), 3526 -3535 (2003) (https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols-naphtofurans-2.pdf)
DOI:10.1021/jm030064v S0022-2623(03)00064-5
Abstract
In studies of the SAR of phenethylamine-type serotonin 5-HT2A receptor agonists, substituted conformationally constrained tetrahydronaphthofurans were designed to investigate the optimal conformation of the 2-aminoethyl moiety. These compounds were tested using in vitro assays for affinity at 5-HT1A, 5-HT2A, and 5-HT2C receptors. The benzofuran-containing analogues, 6a and 6b, had significantly higher affinity for the 5-HT receptors tested than did the benzodihydrofuran-containing compounds, 4a, 4b, 5a, and 5b. The most potent compound (8-bromo-6-methoxy-4,5-dihydro-3H-naphtho [1,8-bc]furan-5-yl) aminomethane, 6b, had Ki values for displacement of [125I]-DOI from 5-HT2A and 5-HT2C cloned rat receptors of 2.6 and 1.1 nM, respectively. Despite their high affinity, the compounds of this naphthofuran series lacked high intrinsic activity at the 5-HT2A receptor as measured using the phosphoinositide hydrolysis assay. The most potent compound in vitro, 6b, was tested in the two-lever drug discrimination assay in rats trained to discriminate LSD from saline, and failed to substitute, a result typical for compounds with low intrinsic activity. Thus, although conformational constraint has led to high-affinity 5-HT2A ligands with partial agonist activity, all of the spatial and steric properties of the ligand necessary for full receptor activation have not yet been identified.
pHarmacist:
This study indicates that these tetrahydronaphthofurans as such, most likely lack clandestine potential/interest. Despite the synthetic procedure being challenging the final products lack in vivo “LSD-like activity”. As authors claim, the novel compounds would not possess "hallucinogenic" activity in man. Important thing is that Nichols group provides nonetheless advancement in key/keyhole/effect relationships:
(1) That the tethering bulk cannot bee tolerated by the receptor
(2) That the “side chain” is not fixed into an appropriate dihedral angle for helical movement in the receptor that would lead to activation
And
(3) That the side chain may require more conformational freedom for receptor activation to occur.
The argument against (3), however, is that LSD, a very rigid molecule, is active.
So, we still don't know a shit in year 2003. But on the other hand, LSD's amide-function-chain is indeed sticking out in conformational freedom. That's probably the one that's the correct "side chain" responsible for the receptor activation and not the one integrated throughout the rigid ring system. Wouldn't you agree? ;)
Rhodium:
...but that won't explain why the small phenethylamines are active, despite that they aren't large enough to reach as far in the receptor. It is much more complex, and different active compounds doesn't even bind in the same conformation...
pHarmacist:
I wonder if anyone explained the magic of position 4 in psychedelic amph/phe. Some say hydrophobic effect others shield against enzymatic attacks and even impact of it on 5-methoxy function (that is very interesting theory btw)... I wonder if there is any rescent study in this regard?
Rhodium:
Oh yes, this has been established, and it it almost entirely due to electronegativity/hydrophobicity, as just any substituent would impede metabolism at the 4-position, but not just any substituent has the right magic. Also, all 3-substituted 2,5-MeO-PEAs bind far less to the 5-HT2A receptor than its 4-substituted analog.
See for example this 1994 paper:
1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: A Potent Serotonin 5-HT2A/2C Agonist
David E. Nichols et. al.
J. Med. Chem. 37, 4346-4351 (1994) (https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols-dotfm.pdf)
Some say hydrophobic effect others shield against enzymatic attacks and even impact of it on 5-methoxy function
Any references for this statement?
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