Identification of the first synthetic allosteric modulator of the CB2receptors and evidence of its efficacy for neuropathic pain relief

The direct activation of cannabinoid receptors (CBRs) results in several beneficial effects, therefore numerous CB1R and CB2R ligands have been developed and tested in vitro and in vivo, but none of them reached an advanced stage of clinical development due to several side effects in particular on the CNS. Medicinal chemistry approaches are now engaged to develop allosteric modulators that might offer a novel therapeutic approach to achieve potential therapeutic benefits avoiding inherent side effects of orthosteric ligands. Here we identify the first ever synthetized positive allosteric modulator (PAM) that targets CB2Rs. The evidence for this was obtained using [3H]CP55940 and [35S]GTPγS binding assays. This finding will be useful for the characterization of allosteric binding site(s) on CB2Rs which will be essential for the further development of CB2R allosteric modulators. Moreover, the new CB2R PAM displayed antinociceptive activity in vivo in an experimental mouse model of neuropathic pain, raising the possibility that it might be a good candidate for clinical development.