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Nichols: Novel Naphtofuran 5-HT2A ligands

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Rhodium:
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:
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:
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:
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:
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.

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