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Nichols: Novel Naphtofuran 5-HT2A ligands

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pHarmacist:
Any references for this statement?

Yes I've got the refs. Lot of things are happening IRL but as soon as I can, I'll post the papers (in couple of days I hope)...

Sorry for the delay...

pHarmacist:
I'm unable to upload any of the full-texts to http://pharmacist8.tripod.com
since I can't log in due to some stupid error (yeah, that's tripod allright) but since you can get them anyways - it dosen't matter much. But I could try again later and see if they've fixed the error.

References:

Hydrophobic effect or lipophilicity is an important determinant of hallucinogenic potency, as noted in an early QSAR study: Barfknecht, C. F.; Nichols, D. E.; Dunn, W. J. J. Med. Chem. 1975, 18, 208. Shulgin and Dyer have also illustrated this for a limited series of 4-alkyl substituted compounds in Shulgin, A. T.; Dyer, D. C. J. Med. Chem. 1975, 18, 1201. Nonetheless, Domelsmith, L. N.; Eaton, T. A.; Houk, K. N.; Anderson, G. A.; Glennon, R. A.; Shulgin, A. T.; Castagnoli, N., Jr.; Kollman, P. A. J . Med. Chem. 1981,24, 1414. and more recently Clare, B. W. J . Med. Chem. 1990, 33, 687. have carried out extensive QSAR analyses which point to the importance of hydrophobicity of the 4-substituent as a determinant of activity. The relationship between hydrophobicity of the 4-substituent and affinity for the [3H]ketanserin-labeled 5-HT2 receptor have also been studied: Seggel, M. R.; Yousif, M. Y.; Lyon, R. A.; Titeler, M.; Roth, B. L.; Suba, E. A.; Glennon, R. A. J . Med. Chem. 1990,33,1032. But of course, hydrophobicity of the 4-substituent alone cannot completely account for the variations noted in biological activity for the various substituents studied (Dolesmith et al; look above). It’s possible that the 5-methoxy function of DOM (and hence the unshared electron pairs of the methoxy oxygen) must adopt a particular conformation at the receptor, where the O-methyl is directed away from the 4-substituent. That is, the 4-methyl group of DOM, through a nonbonded interaction forces the 5-methoxy to lie in an anti conformation, it's a bully. Results of molecular mechanics calculations that illustrate this effect were reported by Dahlbom, R., Nilsson, J. L. G., Eds.; Swedish Pharmaceutical Press: Stockholm, 1985; Vol. 2, pages 103-115.

Rhodium:
Here below are the JMC references you posted, do you think you are able to get that Swedish Pharmaceutical Press ref?

A structure-affinity study of the binding of 4-substituted analogs of 1-(2,5-dimethoxyphenyl)-2-aminopropane at 5-HT2 serotonin receptors
Mark R. Seggel, M. Y. Yousif, Robert A. Lyon, Milt Titeler, Bryan L. Roth, Eva A. Suba, Richard A. Glennon
J. Med. Chem. 33(3); 1032-1036 (1990) (https://www.thevespiary.org/rhodium/Rhodium/pdf/glennon.sar.4-subst.pea.pdf)

Structure-activity correlations for psychotomimetics. 1. Phenylalkylamines: electronic, volume, and hydrophobicity parameters
Brian W. Clare
J. Med. Chem. 33(2); 687-702 (1990) (https://www.thevespiary.org/rhodium/Rhodium/pdf/sar.psychotomimetics-1.pdf)

Photoelectron spectra of psychotropic drugs. 6. Relationships between physical properties and pharmacological actions of amphetamine analogs
L. N. Domelsmith, Thomas A. Eaton, K. N. Houk, G. M. Anderson, , III R. A. Glennon, A. T. Shulgin, N. Castagnoli, Jr. P. A. Kollman
J. Med. Chem. 24(12); 1414-1421 (1981) (https://www.thevespiary.org/rhodium/Rhodium/pdf/drugs.photoelectron.spectra-6.pdf)

Psychotomimetic phenylisopropylamines. 5. 4-Alkyl-2,5-dimethoxyphenylisopropylamines
Alexander T. Shulgin, Donald C. Dyer
J. Med. Chem. 18(12); 1201-1204 (1975) (https://www.thevespiary.org/rhodium/Rhodium/pdf/shulgin.4-alkyl-25-meo-phenylisopropylamines.pdf)

Correlation of psychotomimetic activity of phenethylamines and amphetamines with 1-octanol-water partition coefficients
C. F. Barfknecht, David E. Nichols, W. J. Dunn, III
J. Med. Chem. 18(2); 208-210 (1975) (https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols.logp-pea-sar.pdf)

Rhodium:
Behavioral and serotonin receptor properties of 4-substituted derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane
Richard A. Glennon, Richard Young, Fredrick Benington, Richard D. Morin
J. Med. Chem. 25(10), 1163-1168 (1982) (https://www.thevespiary.org/rhodium/Rhodium/pdf/glennon.4-pos-sar.dof-doi-don.pdf)

I think this is some kind of a landmark article. They measure the serotonin receptor affinities of various 4-substituted 2,5-dimethoxyamphetamines (Substituents include F, H, Br, I, OMe, OEt, Me, Et and NO2 and plot those against the subjective human potency, and they find that they correlate perfectly. They also note that 2-MeO, 3-MeO, 4-MeO and 2,5-MeO-3-Br-amphetamine (the latter one is a DOB isomer) does not substitute for DOM in animal tests)

The paper also includes syntheses of DOI and DON from 2,5-DMA as well as a synthesis of DOF almost from scratch, starting with 2-Fluorohydroquinone, which in turn can be made by an Elbs Persulfate Oxidation of 2-Fluorophenol as directed in Post 453381 (Rhodium: "Synthesis of 2-Fluorinated Hydroquinones", Methods Discourse).

moo:
Thanks Rhodium! Why haven't I dug this up before...

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