Design, Synthesis, and Pharmacological Characterization of Indol-3-ylacetamides, Indol-3-yloxoacetamides, and Indol-3-ylcarboxamides: Potent and Selective CB2 Cannabinoid Receptor Inverse Agonists
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- 作者：Serena Pasquini ; Claudia Mugnaini ; Alessia Ligresti ; Andrea Tafi ; Simone Brogi ; Chiara Falciani ; Valentina Pedani ; Nicol貌 Pesco ; Francesca Guida ; Livio Luongo ; Katia Varani ; Pier Andrea Borea ; Sabatino Maione ; Vincenzo Di Marzo ; Federico Corelli
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：June 14, 2012
- 年：2012
- 卷：55
- 期：11
- 页码：5391-5402
- 全文大小：560K
- 年卷期：v.55,no.11(June 14, 2012)
- ISSN：1520-4804
文摘
In our search for new cannabinoid receptor modulators, we describe herein the design and synthesis of three sets of indole-based ligands characterized by an acetamide, oxalylamide, or carboxamide chain, respectively. Most of the compounds showed affinity for CB2 receptors in the nanomolar range, with Ki values spanning 3 orders of magnitude (377鈥?.37 nM), and moderate to good selectivity over CB1 receptors. Their in vitro functional activity as inverse agonists was confirmed in vivo in the formalin test of acute peripheral and inflammatory pain in mice, in which compounds 10a and 11e proved to be able to reverse the effect of the CB2 selective agonist COR167.