5-HT1D Receptor Agonist Properties of Novel 2-[5-[[(Trifluoromethyl)sulfonyl]oxy]indolyl]ethylamines and Their Use as Synthetic Intermediates
| Autor: | J. C. Mcguire, T. A. Barf, Nabil B. Ghazal, Håkan Wikström, S. J. Peroutka, Michael D. Ennis, Kjell A. Svensson, M. W. Smith, P. de Boer |
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| Přispěvatelé: | Faculty of Science and Engineering |
| Rok vydání: | 1996 |
| Předmět: |
Agonist
Serotonin AUTORECEPTORS Magnetic Resonance Spectroscopy Intrinsic activity POTENT AGONISTS Stereochemistry medicine.drug_class Guinea Pigs Ethylamines CHO Cells Hypothermia Mass Spectrometry 5-Hydroxytryptophan Structure-Activity Relationship chemistry.chemical_compound ANTAGONISTS Cricetinae Drug Discovery Cyclic AMP medicine Animals Humans Receptor PHARMACOLOGY BOVINE CEREBRAL-ARTERIES Sulfonyl chemistry.chemical_classification Acrylamides Trifluoromethyl Molecular Structure Bicyclic molecule DERIVATIVES CENTRAL DOPAMINE Brain Hydroxyindoleacetic Acid Recombinant Proteins Rats BRAIN MEMBRANES chemistry SEROTONERGIC ACTIVITY Receptors Serotonin Molecular Medicine 5-HT1 receptor Serotonin Antagonists SUMATRIPTAN |
| Zdroj: | Journal of Medicinal Chemistry, 39(24), 4717-4726. AMER CHEMICAL SOC |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm9604890 |
| Popis: | 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 D-2 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 indolylethylamines 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 (K-i 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. |
| Databáze: | OpenAIRE |
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