Author Topic: Nichols: Novel Naphtofuran 5-HT2A ligands  (Read 4668 times)

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Rhodium

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Nichols: Novel Naphtofuran 5-HT2A ligands
« on: July 24, 2003, 04:38:00 PM »
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

  • Guest
Close, but no cigar...
« Reply #1 on: July 28, 2003, 03:23:00 PM »
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

  • Guest
Hmm...
« Reply #2 on: July 28, 2003, 03:51:00 PM »
...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

  • Guest
True...
« Reply #3 on: July 28, 2003, 04:23:00 PM »
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

  • Guest
The magic of the 4-position
« Reply #4 on: July 28, 2003, 10:58:00 PM »
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?

pHarmacist

  • Guest
Refs
« Reply #5 on: August 05, 2003, 11:35:00 AM »
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

  • Guest
refs.
« Reply #6 on: August 11, 2003, 04:36:00 PM »
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

  • Guest
PEA SAR References
« Reply #7 on: August 12, 2003, 08:02:00 PM »
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

  • Guest
Related SAR article, with DOF/DOI/DON synth
« Reply #8 on: August 13, 2003, 08:56:00 PM »
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

  • Guest
Thanks Rhodium! Why haven't I dug this up...
« Reply #9 on: August 14, 2003, 01:52:00 AM »
Thanks Rhodium! Why haven't I dug this up before...


slappy

  • Guest
Read it more carefully...
« Reply #10 on: August 14, 2003, 06:47:00 PM »
If you read the Nichols article very carefully, they kind of "say" that it is not active in humans... in so many words at least. You just have to understand how they operate.

Another interesting article was just published on JMC ASAP:

http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jm030205t



A Novel and Selective 5-HT2 Receptor Agonist with Ocular Hypotensive Activity: (S)-(+)-1-(2-Aminopropyl)-8,9-dihydropyrano[3,2-e]indole

Basically, they make 4,5-dihydropyran fused AMT. Then they compare activity to DMT, 5-MeO-DMT, and DOI.

Rhodium

  • Guest
DOF and ASAP article
« Reply #11 on: August 14, 2003, 09:36:00 PM »
1) I put together a complete document from the bits and pieces above to give a full

Synthesis of DOF

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/dof.html)

2) I uploaded the full article mentioned above by Slappy to my page:

A Novel and Selective 5-HT2 Receptor Agonist with Ocular Hypotensive Activity: (S)-(+)-1-(2-Aminopropyl)-8,9-dihydropyrano[3,2-e]indole
Jesse A. May, Hwang-Hsing Chen, Andrew Rusinko, Vincent M. Lynch, Najam A. Sharif, and Marsha A. McLaughlin

J. Med. Chem.; 2003; ASAP Web Release Date: 08-Aug-2003

(https://www.thevespiary.org/rhodium/Rhodium/pdf/45-trimethylenoxy-amt.pdf)
DOI:

10.1021/jm030205t





Abstract

Serotonin 5-HT2 receptor agonists have recently been shown to be effective in lowering intraocular pressure in nonhuman primates and represent a potential new class of antiglaucoma agents. As part of an effort to identify new selective agonists at this receptor, we have found that (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole (AL-37350A, 11) has high affinity and selectivity (>1000-fold) for the 5-HT2 receptor relative to other 5-HT receptors. More specifically, 11 is a potent agonist at the 5-HT2A receptor (EC50 = 28.6 nM, Emax = 103%) that is comparable to serotonin. Evaluation of 11 in conscious ocular hypertensive cynomolgus monkeys showed this compound to be efficacious in reducing intraocular pressure (13.1 mmHg, -37%). Thus, 11 is a potent full agonist with selectivity for the 5-HT2 receptor and is anticipated to serve as a useful tool in exploring the role of the 5-HT2 receptor and its effector system in controlling intraocular pressure.

Rhodium

  • Guest
Phenylalkylamine Serotonin Receptor Affinities
« Reply #12 on: August 15, 2003, 03:44:00 PM »
Serotonin receptor affinities of psychoactive phenalkylamine analogs
Richard A. Glennon, Stephen M. Liebowitz, George M. Anderson, III

J. Med. Chem. 23(3); 294-299 (1980)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/glennon.pea.receptor.affinities.pdf)

The article compares a large selection of substituted PEA's and amphetamines and measure their serotonin receptor affinities, and also the following (taken from

Post 306472

(poix: "Phenylalkylamine Serotonin Receptor Affinities", Novel Discourse)
):

The 'Serotonin Receptor Affinities of Psychoactive Phenalkyamine Analogues' article in JMC 1980, 23, 294-299 has some experimental section on 2,5-dimethoxy-3-methyl benzaldehyde and 2,5-dimethoxy-3-bromo benzaldehyde as well as serotonin affinities of the two aminopropane drugs.

The sad things is that they score only 5.33 ±0.06 for the Me analogue and 5.27 ±0.03 for the bromo one on the pA2 value. DOM has an affinity of 7.12±0.07 and so the affinity of 2,5-dimeo-3-Me-A is more than 60 time less than DOM, even less active than mescaline (5.65±0.10)!

Maybe the rat stomach fundus doesn't fully compare with human 5-HTP and these compound will show to be active or maybe they aren't at all. They may be active in some other way, non psychedelic one, but only human trial will tell us.

pHarmacist

  • Guest
serotonin receptor topography
« Reply #13 on: September 16, 2003, 02:11:00 PM »
Here below are the JMC references you posted, do you think you are able to get that Swedish Pharmaceutical Press ref?

Use of chemical approaches to probe serotonin receptor topography

DAVID E. NICHOLS

Acta Pharmaceutica Suecia Suppl. 1985:2

(http://pharmacist.the-hive.tripod.com/nichols.pdf)

Presented in 8th International Symposium on Medicinal Chemistry - edited by Richard Dahlbom and J Lars G Nilsson: Dahlbom, R., Nilsson, J. L. G., Eds.; Swedish Pharmaceutical Press: Stockholm, 1985; Vol. 2, pages 103-115.



pHarmacist

  • Guest
Interaction of halluc. agents with 5-HT receptors
« Reply #14 on: September 16, 2003, 09:53:00 PM »
And a little bonus-article from another heavyweighter:

RICHARD A. GLENNON

Acta Pharmaceutica Suecia Suppl. 1985:2

(http://pharmacist-hive.tripod.com/glennon.pdf)


pHarmacist

  • Guest
QSAR on 37 phenylalkylamines
« Reply #15 on: October 09, 2003, 02:25:00 PM »
QSAR study with steric (MTD), electronic and hydrophobicity parameters on psychotomimetic phenylalkylamines
Mracec M. ; Mracec M. ; Kurunczi L. ; Nusser T. ; Simon Z. ; Naray-Szabo G.

Journal of Molecular Structure (Theochem) 367 (1996) 139-149

(http://pharmacist.the-hive.tripod.com/hungary37qsar.pdf)

Abstract: Multiple linear regression analysis has been used to identify the most important properties relevant to psychotomimetic activity displayed by 37 phenylalkylamines. Using the minimal topologic differences (MTD) parameter, lipophilicity (log P, calculated by using ð Hansch substituent terms), average electrostatic field (AEF) and electronic descriptors, lowest unoccupied molecular orbital energies (ELUMO) and net atomic charges (obtained from AM1 calculations), good correlations with biological activity were obtained (R2 = 0.79-0.92). Cross-validation procedure was applied indicating a good predictability of the proposed models (R2cv = 0.67-0.81).


Rhodium

  • Guest
How do you make use of a QSAR study?
« Reply #16 on: October 09, 2003, 10:29:00 PM »
How do you make use of a QSAR like that to predict the approximate potency of novel analogs? Could someone write me a short tutorial?

Lilienthal

  • Guest
Such studies don't provide you with any new...
« Reply #17 on: October 10, 2003, 11:07:00 AM »
Such studies don't provide you with any new information if done for nearly identical compounds where every substituent has already been tested. Especially it doesn't give you detailed information of steric requirements. You can see that hydrophilicity at the 4-position is an important predictor without such a QSAR...
The result of the QSAR should be a long formula with molecule and group specific constants, just fill them in...

pHarmacist

  • Guest
qsar
« Reply #18 on: October 10, 2003, 07:26:00 PM »
The result of the QSAR should be a long formula with molecule and group specific constants, just fill them in...

Lili, are you thinking of Hanch analysis; log(1/C) = a(parameter) + b(electronic parameter) + c(steric parameter) + d(other descriptor)

That is a part of what authors also used in the above paper that I posted - MLR (multiple linear regresion).

But the fun part is the whole pioneer discovery of QSAR. I don't recall the name of the pioneers but they observed that the anesthetic potency of simple organic molecules increases lineary with their lipophilicity coeficients (P). Later on, the master himself Hanch expressed the biological activity as the log of 1/concentration or dose [log(1/C) or pC]. Today there are tons of parameters, for instance I've never heard of Minimal Topologic Differences prior to reading the paper I posted.


longimanus

  • Guest
QSAR vs. Molecular Modeling of 5-HT receptors
« Reply #19 on: December 24, 2003, 03:14:00 PM »
A couple of days ago I also thought that the proper QSAR would solve the enigma.
 But now it is different. I found some articles about the three-dimentional models of 5-HT2A receptor and understood that it`s something really complex. Even more than I thought.
 
 So, here are the articles:
  

None

(http://www.jbc.org/cgi/reprint/270/28/16683.pdf)
  

None

(http://molpharm.aspetjournals.org/cgi/reprint/58/5/877.pdf)
 
 And after you have read the above look at
    

this

(http://www.bio-balance.com/BB5.html)

 Is everything clear. Because I`m able to kill someone to get X-Ray images of 5-HT2 serotonin receptors.
  
    The saga continues.