1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: a potent serotonin 5-HT2A/2C agonist.
D E Nichols, S Frescas, Danuta Marona‐lewicka, X Huang, B L Roth, Gary A. Gudelsky, J F Nash
Journal of Medicinal Chemistry December 9, 1994 DOI: 10.1021/jm00051a011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical pharmacology study (receptor binding, drug discrimination, and cell-based assays) Peer reviewed |
|---|---|
| Population | Rats (cortex tissue and rats trained to discriminate saline from LSD tartrate); cultured cells expressing 5-HT2A or 5-HT2C receptors |
| Interventions | 1-(2 2-(2 serotonin (5-HT) LSD tartrate |
| Measures | [3H]ketanserin binding, [125I]-3-labeled 5-HT2A/2C binding, two-lever drug discrimination assay, [3H]inositol monophosphate accumulation |
| Topics | Serotonin |
| Key points | Compounds 5 and 6 bound 5-HT2A/2C sites in rat cortex with affinity comparable to or higher than their bromo or iodo analogs and had comparable or slightly greater potency in the LSD drug discrimination assay. Both were full agonists at 5-HT2C, but at 5-HT2A compound 6 was only half as potent as compound 5, which the authors propose may partly explain the higher in vivo potency of alpha-methyl compounds in this series. |
Abstract
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.
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Citations in the library
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