5-HT1D receptor agonist properties of novel 2-[5-[[(trifluoromethyl)sulfonyl]oxy]indolyl]ethylamines and their use as synthetic intermediates

Journal of Medicinal Chemistry
T A BarfM W Smith

Abstract

2-[5-[[(trifluoromethyl)sulfonyl]oxy]-1H-indol-3-yl]ethylamine (18), its N,N-di-n-propyl (12), N,N-diethyl (13), and N,N-dimethyl (14) derivatives, and 4-[3-[2-(N,N-dimethylamino)ethyl]-1H-indol-3-yl]-N-(p-methoxybenzyl) acrylamide (GR46611, 19) were synthesized and tested for binding affinities to cloned 5-HT1A, 5-HT1D alpha, 5-HT1D beta, and D2 receptors. In addition, the intrinsic efficacy was measured as the reduction of forskolin-stimulated cAMP in cells transfected with 5-HT1D alpha and 5-HT1D beta receptors in vitro. The 5-substituted indolyethylamines investigated displayed agonist activity at the 5-HT1D receptors with varying degrees of preference for the 5-HT1D alpha vs the 5-HT1D beta receptors. The primary amine and N,N-dimethyl substitution seemed to be optimal for 5-HT1D alpha affinity. Furthermore, the N,N-diethyl (13) and N,N-dimethyl (14) derivatives showed a 10-25 times preference for the 5-HT1D alpha vs the 5-HT1D beta receptor. In addition, all of the novel compounds showed affinity for the 5-HT1A receptor in vitro (Ki values ranging from 18 to 40 nM). The most promising derivative 14 was virtually devoid of central 5-HT1A agonist activity in rats, as determined by in vivo biochemical assays. Paradoxically, ...Continue Reading

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Citations

Jun 15, 2000·Bioorganic & Medicinal Chemistry Letters·C Q MengA Slassi
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·I D KuntzP A Kollman
Jan 30, 2016·ACS Chemical Neuroscience·Jo SourbronPeter A M de Witte
May 21, 2004·The Journal of Pharmacology and Experimental Therapeutics·Baojun GuPaul C Dolber
Mar 18, 2010·ChemMedChem·Alessia CarocciCarlo Franchini
Apr 25, 2002·Journal of the American Chemical Society·Sandra J RosenthalRandy D Blakely
Aug 2, 2007·Journal of Medicinal Chemistry·Alessio MoriconiMarcello Allegretti

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