Alkyl indole-based cannabinoid type 2 receptor tools: Exploration of linker and fluorophore attachment

• Published in: European journal of medicinal chemistry Vol. 145; pp. 770 - 789
• Main Authors: Cooper, Anna G., MacDonald, Christa, Glass, Michelle, Hook, Sarah, Tyndall, Joel D.A., Vernall, Andrea J.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 10.02.2018; Elsevier
• Subjects: 6-(((4,4-difluoro-5-(2-thienyl)-4-bora-3a,4a-diaza-sindacene-3-yl)styryloxy)acetyl) aminohexanoic acid, succinimidyl ester; Alkyl indole; BODIPY 630/650-X-OSu; Cannabinoid; Cannabinoid type 2 receptor; Chemistry, Medicinal; Fluorescent probe; G protein-coupled receptor; Life Sciences & Biomedicine; PEG; Pharmacology & Pharmacy; polyethylene glycol; Science & Technology; G protein-coupled receptor; polyethylene glycol; PEG; BODIPY 630/650-X-OSu; Cannabinoid type 2 receptor; Fluorescent probe; Alkyl indole; 6-(((4,4-difluoro-5-(2-thienyl)-4-bora-3a,4a-diaza-sindacene-3-yl)styryloxy)acetyl) aminohexanoic acid, succinimidyl ester; Cannabinoid; CB2 RECEPTOR; ENDOCANNABINOID SYSTEM; INFRARED FLUORESCENT-PROBE; PROTEIN-COUPLED RECEPTORS; CRYSTAL-STRUCTURES; INVERSE AGONISTS; LIGANDS; ADENOSINE A RECEPTOR; BIOLOGICAL EVALUATION; BINDING
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.11.076

Cannabinoid type 2 (CB2) receptor continues to emerge as a promising drug target for many diseases and conditions. New tools for studying CB2 receptor are required to further inform how this receptor functions in healthy and diseased states. The alkyl indole scaffold is a well-recognised ligand for cannabinoid receptors, and in this study the indole C5-7 positions were explored for linker and fluorophore attachment. A new high affinity, CB2 receptor selective inverse agonist was identified (16b) along with a general trend of C5-substituted indoles acting as agonists versus C7-substituted indoles acting as inverse agonists. The indole C7 position was found to be the most tolerant to linker extension and resulted in a high affinity inverse agonist with a medium length linker (19). Although a high affinity fluorescent ligand for CB2 receptor was not identified in this study, the indole C7 position shows great promise for fluorophore or probe attachment. [Display omitted] •A C7-long linker aminoalkyl indole is a promising lead for a fluorescent probe.•A new high affinity, selective CB2 receptor inverse agonist was discovered.•Aminoalkyl indoles modified at C5 predominantly acted as agonists at CB2 receptor.•Aminoalkyl indoles modified at C7 predominantly acted as inverse agonists.