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

  1. Author:
    Fung, S.
    Xu, C.
    Hamel, Ernest
    Wager-Miller, J. B.
    Woodruff, G.
    Miller, A.
    Sanford, C.
    Mackie, K.
    Stella, N.

  2. Author Address

    Department of Pharmacology, University of Washington, 1959 NE Pacific Way, Seattle, WA, United States; Graduate Program in Neurobiology and Behavior, University of Washington, 1959 NE Pacific St., Seattle, WA, United States.;Department of Pharmacology, University of Washington, 1959 NE Pacific Way, Seattle, WA, United States.;Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States.;Department of Psychiatry and Behavioral Sciences, University of Washington, 1959 NE Pacific Way, Seattle, WA, United States.;Department of Pharmacology, University of Washington, 1959 NE Pacific Way, Seattle, WA, United States; Department of Psychological and Brain Sciences, Indiana University, 702 N. Walnut Grove Ave, Bloomington, IN 47405, United States. Electronic address: nstella@uw.edu.
    1. Year: 2017
    2. Date: Jan
    3. Epub Date: 11/12/2016
  2. Journal: Pharmacological Research
    1. 115
    2. Pages: 233-241
  4. Type of Article: Article
  5. ISSN: 1043-6618
  1. Abstract:

    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 52nM and appears to have a weaker affinity for the colchicine site of tubulin (Kd=3.2muM) 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.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.phrs.2016.10.025
  3. PMID: 27832960
  4. View record in Web of Science®
  5. WOS: 000392790400022

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