Author Topic: Nichols: Novel Naphtofuran 5-HT2A ligands  (Read 4093 times)

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7is

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Ebersole BJ, Visiers I, Weinstein H, Sealfon...
« Reply #20 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:

http://nic-nac-project.de/~tajkor/20.pdf




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:

http://nic-nac-project.de/~tajkor/21.pdf


scarmani

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Another QSAR
« Reply #21 on: February 12, 2004, 07:19:00 AM »
QSAR studies on psychotomimetic phenylalkylamines
Mamta Thakur, Abhilash Thakurb and Padmakar V. Khadikarc

None

(http://www.streamload.com/scarmani/5HT/QSAR_studies_on_psychotomimetic_phenylalkylamines.pdf)

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...)


Rhodium

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Nichols Phenethylamine SAR
« Reply #22 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)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols-pea-sar.pdf)


7is

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W. H. Vogel and B. D.
« Reply #23 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


Ganesha

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QSAR
« Reply #24 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



Summary

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.


Rhodium

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Nichols: Tetrahydro-1-Benzoxepin Analogs
« Reply #25 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)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols-tetrahydrobenzoxepins.pdf)

Abstract
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.


Rhodium

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Nichols: SAR of branched/chiral 4-substituents
« Reply #26 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)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols-branched.4-substituents.pdf)

Abstract
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)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols-chiral.4-substituents.pdf)

Abstract
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.


Rhodium

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First Computer Model of the 5-HT2A Receptor
« Reply #27 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)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/nichols/nichols-5-ht2a.model.in.silico.pdf)

Abstract
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.


longimanus

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Multiple Conformations of Human 5-HT2A Receptors
« Reply #28 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

(http://molpharm.aspetjournals.org/cgi/reprint/60/4/690.pdf)

Abstract
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.

longimanus

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ACNP`s Serotonin
« Reply #29 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

http://www.acnp.org/g5/p/SCH2_15-34.pdf


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.