Synthesis, biological activity and molecular modeling of new biphenylic carboxamides as potent and selective CB2 receptor ligands

•We report the study of a series of biphenylic carboxamides as new CB2 ligands.•Good CB2 affinity/selectivity was reached with some 3-n-butyl-substituted compounds.•The 3-n-butyl-substituted compounds proved to be CB2 neutral antagonists.

The CB2 receptor is a therapeutic target of increasing importance for several diseases, including pain, inflammation, neurodegeneration, cancer and osteoporosis. While several compounds showing CB2-selective agonist or inverse agonist properties have been developed, only few CB2 receptor selective neutral antagonists are actually known. Such type of compounds could be useful to study more in depth the role of the CB2 receptor, because they lack the ability to counteract its “constitutive” activity. Here we describe the synthesis and biological activity of a series of biphenylic carboxamides as a new class of CB2 receptor selective ligands. In binding assays, one of these compounds showed good CB2 receptor affinity and selectivity (Ki = 11.48 nM; Selectivity Index = 130). Furthermore, in functional assays, the same compound showed a very interesting pharmacological profile as CB2 receptor selective neutral antagonist. These results pave the way to further developments, including structural optimization, with the aim to obtain more potent CB2 receptor ligands with this peculiar feature.

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