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 January 1, 1996 DOI: 10.1021/jm960199j via OpenAlex
Summary
A series of eight new phenylalkylamine derivatives with conformationally restricted dihydrofuran rings were synthesized and tested in rats. One compound, 7b, substituted for LSD in a drug discrimination assay with an ED50 of 61 nmol/kg and bound to 5-HT2 receptors with nanomolar to subnanomolar affinity, making it among the most potent hallucinogen-like phenylalkylamines reported. All compounds with a hydrophobic substituent para to the alkylamine side chain matched or exceeded the activity of flexible parent compounds. The results suggest the dihydrofuran rings model the active binding conformations of methoxy groups and provide information about agonist binding topography in serotonin 5-HT2 receptors.
Study at a glance
| 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 |
| Interventions | 8-substituted 1-(2 3 6 7-tetrahydrobenzo[1 2-b:4 |
| Dose | 0.08 mg/kg LSD tartrate (training dose); 61 nmol/kg ED50 for 7b |
| Topics | Mescaline Serotonin |
| Keywords | Hallucinogen Ketanserin Stereochemistry 5-ht2 receptor |
| Citations | 106 |
| Key finding | 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.