1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: A Potent Serotonin 5-HT2A/2C Agonist

David E. Nichols, Stewart Frescas, Danuta Marona-Lewicka, Xuemei Huang, Bryan L. Roth, Gary A. Gudelsky, J. Frank Nash

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

A method was found to synthesize 1-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane, 5, and its des-α-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 α-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 α-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 α-methyl-substituted compounds in this series.

Original languageEnglish (US)
Pages (from-to)4346-4351
Number of pages6
JournalJournal of Medicinal Chemistry
Volume37
Issue number25
DOIs
StatePublished - Dec 1 1994

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Serotonin 5-HT2 Receptor Agonists
Receptor, Serotonin, 5-HT2A
Receptor, Serotonin, 5-HT2C
Serotonin
Inositol
Ketanserin
Serotonin Receptor Agonists
Lysergic Acid Diethylamide
Amphetamine
Cultured Cells
Pharmaceutical Preparations
1-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Nichols, D. E., Frescas, S., Marona-Lewicka, D., Huang, X., Roth, B. L., Gudelsky, G. A., & Nash, J. F. (1994). 1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: A Potent Serotonin 5-HT2A/2C Agonist. Journal of Medicinal Chemistry, 37(25), 4346-4351. https://doi.org/10.1021/jm00051a011
Nichols, David E. ; Frescas, Stewart ; Marona-Lewicka, Danuta ; Huang, Xuemei ; Roth, Bryan L. ; Gudelsky, Gary A. ; Nash, J. Frank. / 1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane : A Potent Serotonin 5-HT2A/2C Agonist. In: Journal of Medicinal Chemistry. 1994 ; Vol. 37, No. 25. pp. 4346-4351.
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abstract = "A method was found to synthesize 1-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane, 5, and its des-α-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 α-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 α-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 α-methyl-substituted compounds in this series.",
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Nichols, DE, Frescas, S, Marona-Lewicka, D, Huang, X, Roth, BL, Gudelsky, GA & Nash, JF 1994, '1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: A Potent Serotonin 5-HT2A/2C Agonist', Journal of Medicinal Chemistry, vol. 37, no. 25, pp. 4346-4351. https://doi.org/10.1021/jm00051a011

1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane : A Potent Serotonin 5-HT2A/2C Agonist. / Nichols, David E.; Frescas, Stewart; Marona-Lewicka, Danuta; Huang, Xuemei; Roth, Bryan L.; Gudelsky, Gary A.; Nash, J. Frank.

In: Journal of Medicinal Chemistry, Vol. 37, No. 25, 01.12.1994, p. 4346-4351.

Research output: Contribution to journalArticle

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T1 - 1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane

T2 - A Potent Serotonin 5-HT2A/2C Agonist

AU - Nichols, David E.

AU - Frescas, Stewart

AU - Marona-Lewicka, Danuta

AU - Huang, Xuemei

AU - Roth, Bryan L.

AU - Gudelsky, Gary A.

AU - Nash, J. Frank

PY - 1994/12/1

Y1 - 1994/12/1

N2 - A method was found to synthesize 1-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane, 5, and its des-α-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 α-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 α-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 α-methyl-substituted compounds in this series.

AB - A method was found to synthesize 1-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane, 5, and its des-α-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 α-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 α-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 α-methyl-substituted compounds in this series.

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