1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: A Potent Serotonin 5-HT2A/2C Agonist
| Autor: | B. L. Roth, Gary A. Gudelsky, J. F. Nash, Xuemei Huang, David E. Nichols, Danuta Marona-Lewicka, Stewart Frescas |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
Male
Agonist Serotonin Phenethylamine Ketanserin Stereochemistry medicine.drug_class Phosphatidylinositols Tritium Binding Competitive Hippocampus Cell Line Iodine Radioisotopes Rats Sprague-Dawley Mice chemistry.chemical_compound Discrimination Psychological Phenethylamines Drug Discovery medicine Animals Amphetamine Receptor 8-Hydroxy-2-(di-n-propylamino)tetralin Trifluoromethyl Chemistry 5-HT2 receptor 3T3 Cells Frontal Lobe Rats Serotonin Receptor Agonists Receptors Serotonin Molecular Medicine medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 37:4346-4351 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00051a011 |
| Popis: | A method was found to synthesize 1-(2,5-dimethoxy-4-(trifluoromethyl) phenyl)-2-aminopropane, 5, and its des-alpha-methyl congener 2-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)aminoethane, 6, the trifluoromethyl analogs of substituted hallucinogenic phenethylamine derivatives such as 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3, DOI) that are potent 5-HT2A/2C agonists. In our hands, 5 and 6 have proven to have affinity for [3H]ketanserin or [125I]-3-labeled 5-HT2A/2C sites in rat cortex comparable to or higher than the analogous bromo or iodo analogs. Similarly, 5 and 6 had potency comparable to or slightly greater than that of their bromo or iodo congeners in the two-lever drug discrimination assay in rats trained to discriminate saline from LSD tartrate. The agonist properties of 5 and 6 were evaluated by measuring the accumulation of [3H]inositol monophosphate in cultured cells selectively expressing either 5-HT2A or 5-HT2C receptors. In comparison to serotonin (5-HT), compounds 3 (DOI), 5, and 6 were equally efficacious and full agonists at the 5-HT2C receptor. Similarly, 3 and 5 produced equivalent responses at the 5-HT2A receptor as compared to 5-HT. In contrast, 6, the alpha-desmethyl analog of 5, was only half as potent at stimulating inositol monophosphate accumulation at the 5-HT2A receptor. In conclusion, the title compound 5 and its alpha-desmethyl congener 6 appear to be the most potent of the so-called hallucinogenic amphetamine 5-HT agonists reported to date. Further, the reduced efficacy of 6 at the 5-HT2A receptor may offer at least a partial explanation for the observed higher in vivo potencies of alpha-methyl-substituted compounds in this series. |
| Databáze: | OpenAIRE |
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