Novel indole-based compounds that differentiate alkylindole-sensitive receptors from cannabinoid receptors and microtubules: Characterization of their activity on glioma cell migration.
Indole-based compounds, such as the alkyl-indole (AI) compound WIN55212-2, activate the cannabinoid receptors, CB1and 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 CB1and CB2receptors 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 Kdof 52nM and appears to have a weaker affinity for the colchicine site of tubulin (Kd=3.2μM) and does not bind CB1/CB2receptors. 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.
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.
Susan
S
Fung
Department of Pharmacology, University of Washington, 1959 NE Pacific Way, Seattle, WA, United States.
Cong
C
Xu
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.
Ernest
E
Hamel
Department of Psychiatry and Behavioral Sciences, University of Washington, 1959 NE Pacific Way, Seattle, WA, United States.
James B
JB
Wager-Miller
Department of Pharmacology, University of Washington, 1959 NE Pacific Way, Seattle, WA, United States.
Grace
G
Woodruff
Department of Pharmacology, University of Washington, 1959 NE Pacific Way, Seattle, WA, United States.
Aaron
A
Miller
Department of Pharmacology, University of Washington, 1959 NE Pacific Way, Seattle, WA, United States.
Christina
C
Sanford
Department of Psychiatry and Behavioral Sciences, University of Washington, 1959 NE Pacific Way, Seattle, WA, United States.
Ken
K
Mackie
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.
Nephi
N
Stella
D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001667:Binding, Competitive / Q000502:physiology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D003078:Colchicine / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D014404:Tubulin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C030374:indole; D003078:Colchicine
Alkyl-indole; Cannabinoids; GBM; Glioma; Migration