title: Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators.
abstract: Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes. In spite of the theoretical potential of CB1 NAMs, published in vivo studies have generally not been able to demonstrate the expected therapeutically-relevant CB1-mediated effects. Thus, a greater range of molecular tools are required to allow definitive elucidation of the effects of CB1 allosteric modulation. In this study, we show a novel series of indole sulfonamides. Compounds 5e and 6c (ABD1075) had potencies of 4 and 3nM respectively, and showed good oral exposure and CNS penetration, making them highly versatile tools for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.
authors.affiliation: Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. Electronic address: i.greig@abdn.ac.uk.
authors.forename: Iain R
authors.initials: IR
authors.lastname: Greig
authors.affiliation: Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK; Department of Pharmacology and Toxicology, University of Toronto and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Baillie
authors.affiliation: Laboratory of Supramolecular Chemistry, School of Natural and Computing Sciences, University of Aberdeen, Aberdeen AB24 3UE, Scotland, UK; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Abdelrahman
authors.affiliation: Laboratory of Supramolecular Chemistry, School of Natural and Computing Sciences, University of Aberdeen, Aberdeen AB24 3UE, Scotland, UK.
authors.forename: Laurent
authors.initials: L
authors.lastname: Trembleau
authors.affiliation: Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK; Department of Pharmacology and Toxicology, University of Toronto and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Ross
mesh_terms: D000494:Allosteric Regulation; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D063385:Cannabinoid Receptor Modulators; D007211:Indoles; D013449:Sulfonamides; C030374:indole
keywords: CB1 NAM; Cannabinoid; Indole sulfonamide; Negative allosteric modulator