title: Structure-activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators.
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.
authors: Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Thuy
authors: T
authors: Nguyen
authors: Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Nadezhda
authors: N
authors: German
authors: Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Ann M
authors: AM
authors: Decker
authors: Department of Pharmacology and Toxicology, University at Buffalo, the State University of New York, Buffalo, New York 14214, United States.
authors: Jun-Xu
authors: JX
authors: Li
authors: Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Jenny L
authors: JL
authors: Wiley
authors: Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Brian F
authors: BF
authors: Thomas
authors: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
authors: Terry P
authors: TP
authors: Kenakin
authors: Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Yanan
authors: Y
authors: Zhang
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D007211:Indoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2
keywords: Allosteric modulators; CB1 receptor; Org compounds; Structure–activity relationship