The Vespiary

The Hive => Serious Chemistry => Topic started by: Rhodium on July 24, 2003, 04:38:00 PM

Title: Nichols: Novel Naphtofuran 5-HT2A ligands
Post by: Rhodium 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) (


10.1021/jm030064v S0022-2623(03)00064-5 (



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.
Title: Close, but no cigar...
Post by: pHarmacist 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


(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?  ;)

Title: Hmm...
Post by: Rhodium 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...
Title: True...
Post by: pHarmacist 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?

Title: The magic of the 4-position
Post by: Rhodium 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) (


Some say hydrophobic effect others shield against enzymatic attacks and even impact of it on 5-methoxy function

Any references for this statement?
Title: Refs
Post by: pHarmacist 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...

Title: refs.
Post by: pHarmacist on August 11, 2003, 04:36:00 PM
I'm unable to upload any of the full-texts to (

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.


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.

Title: PEA SAR References
Post by: Rhodium 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) (


Structure-activity correlations for psychotomimetics. 1. Phenylalkylamines: electronic, volume, and hydrophobicity parameters
Brian W. Clare

J. Med. Chem. 33(2); 687-702 (1990) (


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) (


Psychotomimetic phenylisopropylamines. 5. 4-Alkyl-2,5-dimethoxyphenylisopropylamines
Alexander T. Shulgin, Donald C. Dyer

J. Med. Chem. 18(12); 1201-1204 (1975) (


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) (

Title: Related SAR article, with DOF/DOI/DON synth
Post by: Rhodium 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) (


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)
Title: Thanks Rhodium! Why haven't I dug this up...
Post by: moo on August 14, 2003, 01:52:00 AM
Thanks Rhodium! Why haven't I dug this up before...

Title: Read it more carefully...
Post by: slappy 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: (

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.
Title: DOF and ASAP article
Post by: Rhodium 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 (


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 (


10.1021/jm030205t (



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.
Title: Phenylalkylamine Serotonin Receptor Affinities
Post by: Rhodium 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) (


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.
Title: serotonin receptor topography
Post by: pHarmacist 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


Acta Pharmaceutica Suecia Suppl. 1985:2 (


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.

Title: Interaction of halluc. agents with 5-HT receptors
Post by: pHarmacist on September 16, 2003, 09:53:00 PM
And a little bonus-article from another heavyweighter:


Acta Pharmaceutica Suecia Suppl. 1985:2  (


Title: QSAR on 37 phenylalkylamines
Post by: pHarmacist 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 (


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).

Title: How do you make use of a QSAR study?
Post by: Rhodium 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?
Title: Such studies don't provide you with any new...
Post by: Lilienthal 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...
Title: qsar
Post by: pHarmacist 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.

Title: QSAR vs. Molecular Modeling of 5-HT receptors
Post by: longimanus 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 (


None (

 And after you have read the above look at

this (


 Is everything clear. Because I`m able to kill someone to get X-Ray images of 5-HT2 serotonin receptors.
    The saga continues.
Title: Ebersole BJ, Visiers I, Weinstein H, Sealfon...
Post by: 7is on January 26, 2004, 08:08:00 PM
Ebersole BJ, Visiers I, Weinstein H, Sealfon SC. Molecular basis of partial agonism: orientation of indoleamine ligands in the binding pocket of the human serotonin 5-HT2A receptor determines relative efficacy.  Mol Pharmacol. 2003 Jan; 63(1): 36-43.

Based on experiment and computational simulation, we present a structural explanation for the differing efficacies of indole agonists at the human serotonin 5-HT2A receptor (5HT2AR). We find that serotonin [5-hydroxytryptamine (5-HT)] forms hydrogen-bonds with Ser3.36 in helix 3 and Ser5.46 in helix 5. Disruption of these hydrogen bonds by methyl-substitution of the cationic primary amine or of the backbone N1-amine, respectively, leads to a reduction in agonist efficacy. Computational simulation predicts that mutation of Ser3.36 to Ala should allow a similar interaction with helix 3 both for agonists that have unmodified cationic amine side chains and for those with substituted amines. Experimentally, this mutation was found to largely eliminate the differences in efficacy caused by cationic amine substitution for a series of indole congeners. Similarly, substitution of the N1-amine, which interacts with Ser5.46, reduced efficacy more markedly at the wild-type (WT) than at the Ser5.46Ala mutant receptor. Computational modeling of binding pocket interactions of ligands with WT and mutant receptor constructs demonstrate how the Ser3.36 and Ser5.46 interactions serve to modify the agonist's favored position in the binding pocket. A striking correlation was found between differences in the position assumed by the indole ring and differences in agonist activity. These data support the hypothesis that the position of the agonist interacting with the receptor is influenced by specific interactions in helices 3 and 5 and determines the degree of receptor activation by agonist through a mechanism that is likely to be shared by other G-protein coupled receptors in this class.

Fulltext: (

Gonzalez-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, Weisstaub N, Hen R, Gingrich JA, Sealfon SC. Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci. 2003 Oct 1; 23(26): 8836-43.

Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.

Fulltext: (

Title: Another QSAR
Post by: scarmani on February 12, 2004, 07:19:00 AM
QSAR studies on psychotomimetic phenylalkylamines
Mamta Thakur, Abhilash Thakurb and Padmakar V. Khadikarc

None (


Abstract: Quantitative Structure-Activity Relationship (QSAR) studies on a series of psychotomimetic phenylalkylamines have been made using a combination of Minimum Topological Difference (MTD) method and topological methodology. The topological indices used being a pool of distance-based topological indices. The regression analyses have shown that excellent results are obtained in multiparametric model containing MTD parameters, topological indices in that quantum chemical parameters has to be introduced. The predictive power of the proposed model is discussed on the basis of cross-validation parameters.

(a follow-up effort to the QSAR paper posted above by pHarmacist...)

Title: Nichols Phenethylamine SAR
Post by: Rhodium on March 15, 2004, 07:15:00 PM
Literature Survey:
Structure-Activity Relationships of Phenethylamine Hallucinogens

David E. Nichols

Journal of Pharmaceutical Sciences 70(8), 839-849 (1981) (


Title: W. H. Vogel and B. D.
Post by: 7is on March 26, 2004, 07:23:00 PM
W. H. Vogel and B. D. Evans
Structure-activity-relationships of certain hallucinogenic substances based on brain levels
Life Sciences Volume 20, Issue 10, 15 May 1977, Pages 1629-1635


Title: QSAR
Post by: Ganesha on April 05, 2004, 01:47:00 PM
Journal of Computer-Aided Molecular Design, 16: 611–633, 2002.

QSAR of benzene derivatives: comparison of classical descriptors, quantum theoretic parameters and flip regression, exemplified by phenylalkylamine hallucinogens

Brian W. Clare



A physical model of electronic effects in the QSAR of benzene derivatives, together with a regression technique for finding predictive equations, is presented. The model is simple, based on the quantum theoretic description of the benzene molecule, and accounts for the variance in activity of hallucinogenic phenylalkylamines as well as a classical description in terms of electronic (atomic charge, orbital energy), hydrophobic (Hansch pi) and steric (substituent volume) terms. The new model involves the energies of four pi-like near frontier orbitals and the orientations of their nodes. It is less affected by colinearity than the classical approach. This model more than any other illustrates the essential wave mechanical nature of the interaction of a drug with its receptor, as the pi-like orbitals involved are standing waves of probability of finding an electron in a given location in the field of the atomic nuclei, and have no classical counterpart.

Title: Nichols: Tetrahydro-1-Benzoxepin Analogs
Post by: Rhodium on April 30, 2004, 02:37:00 PM
Conformationally Restricted Tetrahydro-1-Benzoxepin Analogs of Hallucinogenic Phenethylamines
Aaron P Monte, Danuta Marona-Lewicka. Nicholas V. Cozzi, David L. Nelson and David E. Nichols

Med. Chem. Res. 5, 651-663 (1995) (


Tetrahydro-1-benzoxepin analogs of prototypical 4-substituted-2,5-dimethoxyphenylisopropylamines were prepared as agents having restricted conformational mobility in the 2-alkoxy group and alkylamine sidechain. The derivatives were evaluated for their ability to produce a discriminative stimulus in LSD-trained rats using the drug discrimination paradigm, for their affinity for radiolabeled serotonin 5-HT2A and 5-HT1A receptors, and for their ability to inhibit the accumulation of neurotransmitter monoamines in synaptosome preparations. None of the benzoxepins or substituted phenylisopropylamines had significant affinity for monoamine uptake sites. While both series of compounds had comparable low micromolar affinity for 5-HT1A receptors, the benzoxepins had much lower affinity for 5-HT2A receptors than the phenylisopropylamines (300-400 nM vs. ca. 20 nM). Probably reflecting this fact, only one of the benzoxepins fully substituted in the drug discrimination assay, with a potency about one-third that of the phenylisopropylamines tested.

Title: Nichols: SAR of branched/chiral 4-substituents
Post by: Rhodium on May 11, 2004, 06:35:00 PM
Substituent branching in phenethylamine-type hallucinogens: a comparison of 1-[2,5-dimethoxy-4-(2-butyl)phenyl]-2-aminopropane and 1-[2,5-dimethoxy-4-(2-methylpropyl)phenyl]-2-aminopropane
Robert A. Oberlender, Paresh J. Kothari, David E. Nichols, Joseph E. Zabik

J. Med. Chem. 27, 788-792 (1984) (


Two novel hallucinogen analogues related to 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, STP) were synthesized and evaluated in the two-lever drug discrimination paradigm by using 0.08 mg/kg of LSD as the training drug stimulus. The two compounds differ from each other only with respect to the point of branching in the 4-alkyl group. However, pharmacological evaluation revealed a clear difference in potency and degree of LSD generalization for the two isomers. Branching adjacent to the ring, as in the 4-(2-butyl) analogue, may provide steric interference to the formation of the drug-receptor complex, while branching one methylene unit removed from the ring, as in the 4-(2-methylpropyl) analogue, poses less of a steric problem for the drug-receptor interaction. This is consistent with the idea that formation of a charge-transfer complex between the hallucinogen molecule and the receptor may be one of the features of this drug-receptor interaction.
____ ___ __ _

Effect of a Chiral 4-Alkyl Substituent in Hallucinogenic Amphetamines
Robert Oberlender, P. V. Ramachandran, Michael P. Johnson, Xuemei Huang, David E. Nichols

J. Med. Chem. 38, 3593-3601 (1995) (


The potency of hallucinogenic amphetamine derivatives of the 1-(2,5-dimethoxy-4-alkylphenyl)-2-aminopropane type drops dramatically when the length of the 4-alkyl substituent exceeds propyl or when the substituent is branched. This investigation was directed toward evaluating changes in behavioral and biochemical pharmacology resulting from introducing chirality into the 4-alkyl group of such analogues. Two diastereoisomeric derivatives of this class containing a 4-(R or S)-2-butyl substituent, 11a,b, respectively, were studied. A slight but nonsignificant potency difference in d-lysergic acid diethylamide tartrate (LSD)-like discriminative stimulus properties and equal affinity for [125I-(R)-(2,5-dimethoxy-4-iodophenyl)isopropylamine-labeled serotonin 5-HT2A/C radioligand-binding sites were observed. Thus, the portion of the receptor that interacts with the 4-alkyl substituent on hallucinogenic amphetamines does not present a highly asymmetric environment to the ligand. However, since both test drugs had higher binding affinity but lower LSD-like behavioral potency than the prototype compound with a 4-methyl group ((2,5-dimethoxy-4-methylphenyl)isopropylamine, 2), 11a,b may differ in their receptor agonist efficacy from more behaviorally active compounds such as 2.

Title: First Computer Model of the 5-HT2A Receptor
Post by: Rhodium on June 17, 2004, 08:06:00 PM
A homology-based model of the human 5-HT2A receptor derived from an in silico activated G-protein coupled receptor
James J. Chambers, David E. Nichols

Journal of Computer-Aided Molecular Design, 16(7), 511-520 (2002) (


A homology-based model of the 5-HT2A receptor was produced utilizing an activated form of the bovine rhodopsin (Rh) crystal structure. In silico activation of the Rh structure was accomplished by isomerization of the 11-cis-retinal chromophore, followed by constrained molecular dynamics to relax the resultant high energy structure. The activated form of Rh was then used as a structural template for development of a human 5-HT2A receptor model. Both the 5-HT2A receptor and Rh are members of the G-protein coupled receptor (GPCR) super-family. The resulting homology model of the receptor was then used for docking studies of compounds representing a cross-section of structural classes that activate the 5-HT2A receptor, including ergolines, tryptamines, and amphetamines. The ligand/receptor complexes that ensued were refined and the final binding orientations were observed to be compatible with much of the data acquired through both diversified ligand design and site directed mutagenesis.

Keywords: 5-HT2A receptor, G-protein coupled receptor, Ligand binding, Molecular dynamics, Receptor activation.

Title: Multiple Conformations of Human 5-HT2A Receptors
Post by: longimanus on July 24, 2004, 04:15:00 PM
Multiple Conformations of Native and Recombinant Human 5-Hydroxytryptamine2A Receptors Are Labeled by Agonists and Discriminated by Antagonists
 Juan F. Lopez-Gimenez, Maria Villason, Hose Brea, M. Isabel Loza, Jose M. Palacios, Guadalupe Mengod, and M. Teresa Vilaro

Mol Pharmacol 60:690-699, 2001 (


We have expanded previous studies with the 5-hydroxytryptamine (5-HT)2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane [(+/-)-[125I]DOI)in human brain that had shown biphasic competition curves for several 5-HT2A receptor antagonistsby using new selective antagonists of 5-HT2A (MDL100,907) and 5-HT2C (SB242084) receptors together with ketanserin and mesulergine. Autoradiographic competition experiments were performed with these antagonists in human brain regions where (+/-)-[125I]DOI labels almowst exclusively 5-HT2A receptors (frontal cortex and strioisomers). Furthermore, the effect of uncoupling receptor/G protein complexes on antagonist competition was studied with guanosine-5'-(?,?-imido)triphosphate [Gpp(NH)p]. Competition experients with (+/-)-[3H]1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane [(+/-)-[-3H]DOB] were also performed on membranes from Chinese hamster ovary cells (CHOFA4) expressing cloned human 5-HT2A receptors. In both systems, ketanserin and MDL100,907 displayed bihpasic competition profiles, whereas SB242084 and mesulergine competed monophasically. In absence of antagonist, 100 ?M Gpp(NH)p decreased brain (+/-)-[125I]DOI specific binding to by 40 to 50% and (+/-)-[3H]DOB specific binding to CHOFA4 cells by 30%. The remaining agonist-labeled uncoupled sites were still displaced biphasically by ketanserin and MDL100,907, with unaltered affinities. Saturation experiments were performed in CHOFA4 cells. (+/-)-[3H]DOB labeled two sites (Kdh=0.8 nM, Kdl=31.22 nM). Addition of 100 ?M Gpp(NH)p resulted in a single low-affinity (Kd=24.44 nM) site with unchanged Bmax. [3H]5-HT showed no specific binding to 5-HT2A receptors. These results conform with the extended ternary complex model of receptor action that postulates the existance of partly activated receptor conformation(s) (R*) in equilibrium with the ground (R) and the activated G protein-coupled (R*G) conformations. Thus, both in human brain and CHOFA4 cells, the agonists possibly label all three conformations and ketanserin and MDL100,907 recognize with different affinities at least two of these conformations.

 It`s getting more and more complicated. I almost long for the 50s when there`s been almost nothing known about the human brain.
Title: ACNP`s Serotonin
Post by: longimanus on September 11, 2004, 12:17:00 PM
This article possibly deserves it`s own thread but I decided to post it here since our discussion includes the complex problem of the serotonin receptors.

ACNP: Neuropsychopharmacology: The Fifth Generation of Progress: Chapter 2 - Serotonin (

non-printable version! (that doesn`t mean you couldn`t print it ;) )

 I really hope it`ll be of help.(it was for me)

 And, BTW, the whole book is worth the reading.