Identification of the First Synthetic Allosteric Modulator of the CB2 Receptors and Evidence of Its Efficacy for Neuropathic Pain Relief

• Published in: Journal of medicinal chemistry 2019-01, Vol.62 (1), p.276-287
• Main Authors: Gado, Francesca, Di Cesare Mannelli, Lorenzo, Lucarini, Elena, Bertini, Simone, Cappelli, Elena, Digiacomo, Maria, Stevenson, Lesley A, Macchia, Marco, Tuccinardi, Tiziano, Ghelardini, Carla, Pertwee, Roger G, Manera, Clementina
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b00368

The direct activation of cannabinoid receptors (CBRs) results in several beneficial effects; therefore several CBRs ligands have been synthesized and tested in vitro and in vivo. However, none of them reached an advanced phase of clinical development due mainly to side effects 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 synthesized 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.