Novel indole-based compounds that differentiate alkylindole-sensitive receptors from cannabinoid receptors and microtubules: Characterization of their activity on glioma cell migration

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• 作者：Susan Fung^a ; ^b ; Cong Xu^a ; Ernest Hamel^c ; James B. Wager-Miller^d ; Grace Woodruff^a ; Aaron Miller^a ; Christina Sanford^a ; Ken Mackie^d ; Nephi Stella^a ; ^e ; ^{nstella@uw.edu}
• 关键词：2-AG ; arachidonoylglycerol ; AI ; alkylindole ; CB ; cannabinoid ; CB1 ; cannabinoid receptor 1 ; CB2 ; cannabinoid receptor 2 ; CSA4 ; combretastatin A4 ; DBT ; delayed Brain Tumor ; HA ; hemagglutinin ; LPA ; lysophosphatidic acid ; GBM ; glioblastoma multiforme ; SAR ; structure activity relationship ; THC ; tetrahydrocannabinol ; WIN-2 ; WIN55212-2
• 刊名：Pharmacological Research
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：115
• 期：Complete
• 页码：233-241
• 全文大小：1541 K
• 卷排序：115

文摘

Indole-based compounds, such as the alkyl-indole (AI) compound WIN55212-2, activate the cannabinoid receptors, CB1 and CB2, two well-characterized G protein-coupled receptors (GPCR). Reports indicate that several indole-based cannabinoid agonists, including WIN55212-2, lack selectivity and interact with at least two additional targets: AI-sensitive GPCRs and microtubules. Studying how indole-based compounds modulate the activity of these 4 targets has been difficult as selective chemical tools were not available. Here we report the pharmacological characterization of six newly-developed indole-based compounds (ST-11, ST-23, ST-25, ST-29, ST-47 and ST-48) that exhibit distinct binding affinities at AI-sensitive receptors, cannabinoid CB1 and CB2 receptors and the colchicine site of tubulin. Several compounds exhibit some level of selectivity for AI-sensitive receptors, including ST-11 that binds AI-sensitive receptors with a Kd of 52 nM and appears to have a weaker affinity for the colchicine site of tubulin (Kd = 3.2 μM) and does not bind CB1/CB2 receptors. Leveraging these characteristics, we show that activation of AI-sensitive receptors with ST-11 inhibits both the basal and stimulated migration of the Delayed Brain Tumor (DBT) mouse glioma cell line. Our study describes a new series of indole-based compounds that enable the pharmacological and functional differentiation of alkylindole-sensitive receptors from cannabinoid receptors and microtubules.