New cannabinoid receptor antagonists as pharmacological tool

Synthesis and pharmacological evaluation of a new series of cannabinoid receptor antagonists of indazole ether derivatives have been performed. Pharmacological evaluation includes radioligand binding assays with [H]-CP55940 for CB1 and CB2 receptors and functional activity for cannabinoid receptors on isolated tissue. In addition, functional activity of the two synthetic cannabinoids antagonists 18 (PGN36) and 17 (PGN38) were carried out in the osteoblastic cell line MC3T3-E1 that is able to express CB2R upon osteogenic conditions. Both antagonists abolished the increase in collagen type I gene expression by the well-known inducer of bone activity, the HU308 agonist. The results of pharmacological tests have revealed that four of these derivatives behave as CB2R cannabinoid antagonists. In particular, the compounds 17 (PGN38) and 18 (PGN36) highlight as promising candidates as pharmacological tools.
This work was supported from Ministerio de Ciencia e Innovación under Grant RTI2018-096100B-100, Plan Nacional de I + D + I 2013-2016, ISCIII–FEDER (FIS16/00637), Plan de Ciencia, Tecnología e Innovación 2013-2017 and 2018-2022 del Principado de Asturias (GRUPIN14-028, IDI-2018-000152), RedInRen from ISCIII (RD16/0009/0017). Natalia Carrillo López was supported by GRUPIN14-028 and IDI-2018-000152.