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  • Title: Structure-activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators.
    Author: Nguyen T, German N, Decker AM, Li JX, Wiley JL, Thomas BF, Kenakin TP, Zhang Y.
    Journal: Bioorg Med Chem; 2015 May 01; 23(9):2195-2203. PubMed ID: 25797163.
    Abstract:
    A series of substituted 1H-indole-2-carboxamides structurally related to compounds Org27569 (1), Org29647 (2) and Org27759 (3) were synthesized and evaluated for CB1 allosteric modulating activity in calcium mobilization assays. Structure-activity relationship studies showed that the modulation potency of this series at the CB1 receptor was enhanced by the presence of a diethylamino group at the 4-position of the phenyl ring, a chloro or fluoro group at the C5 position and short alkyl groups at the C3 position on the indole ring. The most potent compound (45) had an IC₅₀ value of 79 nM which is ∼2.5 and 10 fold more potent than the parent compounds 3 and 1, respectively. These compounds appeared to be negative allosteric modulators at the CB1 receptor and dose-dependently reduced the Emax of agonist CP55,940. These analogs may provide the basis for further optimization and use of CB1 allosteric modulators.
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