Synthesis and Pharmacological Characterization of a Series of Geometrically Constrained 5-HT2A/2C Receptor Ligands
James J. Chambers, Jason C. Parrish, Niels Jensen, Deborah Kurrasch‐orbaugh, Danuta Marona‐lewicka, David E. Nichols
Journal of Medicinal Chemistry July 1, 2003 DOI: 10.1021/jm030064v (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro and animal behavioral study Peer reviewed |
|---|---|
| Population | Cloned rat receptors and rats trained to discriminate LSD from saline |
| Interventions | 6b 4a 4b 5a |
| Topics | Serotonin |
| Keywords | Stereochemistry Phenethylamine Intrinsic activity Ligand biochemistry Partial agonist In vitro Moiety 5-HT Receptor Benzofuran |
| Citations | 27 |
| Key points | Conformationally constrained naphthofuran compounds had high affinity for 5-HT(2A) receptors but low intrinsic activity, failing to substitute for LSD in rats. |
Abstract
In studies of the SAR of phenethylamine-type serotonin 5-HT(2A) 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-HT(1A), 5-HT(2A), and 5-HT(2C) 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 K(i) values for displacement of [(125)I]-DOI from 5-HT(2A) and 5-HT(2C) 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-HT(2A) 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-HT(2A) 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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 8
- Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology May 1, 2020
- 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. Journal of Medicinal Chemistry September 21, 2006
- Differential phospholipase C activation by phenylalkylamine serotonin 5‐HT2Areceptor agonists Journal of Neurochemistry November 8, 2005
- Comparison of the behavioral responses induced by phenylalkylamine hallucinogens and their tetrahydrobenzodifuran ("FLY") and benzodifuran ("DragonFLY") analogs. Neuropharmacology 2019
- C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT2AReceptor Journal of Medicinal Chemistry June 21, 2006
and 3 more in the library
Cites 6
- Enantiospecific Synthesis and Pharmacological Evaluation of a Series of Super-Potent, Conformationally Restricted 5-HT2A/2C Receptor Agonists Journal of Medicinal Chemistry January 26, 2001
- Dihydrobenzofuran Analogues of Hallucinogens. 4. Mescaline Derivatives Journal of Medicinal Chemistry September 1, 1997
- A Novel (Benzodifuranyl)aminoalkane with Extremely Potent Activity at the 5-HT2A Receptor Journal of Medicinal Chemistry December 1, 1998
- Stereoselective LSD-like Activity in a Series of d-Lysergic Acid Amides of (R)- and (S)-2-Aminoalkanes Journal of Medicinal Chemistry March 1, 1995
- Substituted Naphthofurans as Hallucinogenic Phenethylamine−Ergoline Hybrid Molecules with Unexpected Muscarinic Antagonist Activity Journal of Medicinal Chemistry May 1, 1998
and 1 more in the library