Dihydrobenzofuran Analogues of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups
Aaron Monte, Danuta Marona‐lewicka, Matthew Parker, David B. Wainscott, David L. Nelson, David E. Nichols
Journal of Medicinal Chemistry 1996 DOI: 10.1021/jm960199j (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vivo drug discrimination assay and in vitro radioligand binding assay Peer reviewed |
|---|---|
| Population | Rats (trained to discriminate saline from LSD tartrate) and rat cortical and hippocampal homogenates; also cells expressing cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors |
| Measures | drug discrimination assay, [3H]ketanserin binding, [3H]-8-OH-DPAT binding, [125I]DOI binding |
| Topics | Mescaline Serotonin 5-MeO-DMT |
| Keywords | Hallucinogen Ketanserin Stereochemistry 5-ht2 receptor In vivo Substituent Biological activity Chemical synthesis Radioligand Pharmacology In vitro 5-HT Receptor Biochemistry |
| Citations | 106 |
| Key points | Compound 7b substituted for LSD with an ED50 of 61 nmol/kg and had nanomolar to subnanomolar affinity for 5-HT2 receptors, making it one of the most potent hallucinogen-like phenylalkylamine derivatives reported. |
Abstract
Tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in prototypical hallucinogenic phenylalkylamines 1 and 2. Thus, a series of 8-substituted 1-(2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminoal kanes (7a-e) were prepared and evaluated for activity in the two-lever drug discrimination paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg) and for the ability to displace [3H]ketanserin from rat cortical homogenate 5-HT2A receptors and [3H]-8-OH-DPAT from rat hippocampal homogenate 5-HT1A receptors. In addition, 1-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-am inopropane (7b), which was found to be extremely potent in the rat in vivo assays, was evaluated for its ability to compete with [125I]DOI and [3H]ketanserin binding to cells expressing cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. All of the dihydrofuranyl compounds having a hydrophobic substituent para to the alkylamine side chain had activities in both the in vitro and in vivo assays that equaled or surpassed the activity of the analogous conformationally flexible parent compounds. For example, 7b substituted for LSD in the drug discrimination assay with an ED50 of 61 nmol/kg and had Kj values in the nanomolar to subnanomolar range for the displacement of radioligand from rat and human 5-HT2 receptors, making it one of the most potent hallucinogen-like phenylalkylamine derivatives reported to date. The results suggest that the dihydrofuran rings in these new analogues effectively model the active binding conformations of the methoxy groups of the parent compounds 1 and 2. In addition, the results provide information about the topography and relative orientation of residues involved in agonist binding in the serotonin 5-HT2 receptors.
Comparable studies
Other preclinical and animal studies on mescaline, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Brain mechanisms of hallucinogens and entactogens Humans and rats | 2001 | Review | |
| Effects of hallucinogenic agents mescaline and phencyclidine on zebrafish behavior and physiology Zebrafish (Danio rerio) | 2012 | Experimental study | |
| Lysergic Acid Diethylamide- and Mescaline-Induced Attenuation of the Effect of Punishment in the Rat Rats | 1976 | Experimental study | |
| Transient reinforcing effects of phenylisopropylamine and indolealkylamine hallucinogens in rhesus monkeys Rhesus monkeys with a history of MDMA self-administration | 2004 | Observational cohort | n = 4 |
Citations in the library
Cited by 33
- 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
- Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines Journal of Medicinal Chemistry October 19, 2000
- Pharmacological profile of novel psychoactive benzofurans British Journal of Pharmacology March 13, 2015
- 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. Journal of Medicinal Chemistry September 21, 2006
- Metabolism of designer drugs of abuse: an updated review. Current Drug Metabolism June 1, 2010
and 28 more in the library
Cites 15
- Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. Journal of Pharmacology and Experimental Therapeutics September 1, 1988
- Neuropharmacological reassessment of the discriminative stimulus properties ofd-lysergic acid diethylamide (LSD) Psychopharmacology 1987
- [125I]-2-(2,5-dimethoxy-4-iodophenyl)aminoethane ([125I]-2C-I) as a label for the 5-HT2 receptor in rat frontal cortex. Pharmacology, Biochemistry, and Behavior 1990
- Hallucinogenic agents as discriminative stimuli: a correlation with serotonin receptor affinities. Psychopharmacology 1980
- 2,3-Dihydrobenzofuran analogs of hallucinogenic phenethylamines Journal of Medicinal Chemistry 1991
and 10 more in the library