Portal de Periódicos da CAPES

5-HT 1D Receptor Agonist Properties of Novel 2-[5-[[(Trifluoromethyl)sulfonyl]oxy]indolyl]ethylamines and Their Use as Synthetic Intermediates

1996; American Chemical Society; Volume: 39; Issue: 24 Linguagem: Inglês

10.1021/jm9604890

1520-4804

Tjeerd Barf, Peter de Boer, Håkan Wikström, Stephen J. Peroutka, Kjell Svensson, Michael D. Ennis, Nabil B. Ghazal, James C. McGuire, Martin Smith,

Adenosine and Purinergic Signaling

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-HT1Dα, 5-HT1Dβ, and D2 receptors. In addition, the intrinsic efficacy was measured as the reduction of forskolin-stimulated cAMP in cells transfected with 5-HT1Dα and 5-HT1Dβ receptors in vitro. The 5-substituted indolylethylamines investigated displayed agonist activity at the 5-HT1D receptors with varying degrees of preference for the 5-HT1Dα vs the 5-HT1Dβ receptors. The primary amine and N,N-dimethyl substitution seemed to be optimal for 5-HT1Dα affinity. Furthermore, the N,N-diethyl (13) and N,N-dimethyl (14) derivatives showed a 10−25 times preference for the 5-HT1Dα vs the 5-HT1Dβ 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, 14, like 19, induced a hypothermic response and a decrease in 5-HIAA levels in the prefrontal cortex and hypothalamus in guinea pigs after systemic administration. Sumatriptan failed to produce either of these effects due to a poor brain penetration.