NOVEL DIARYL UREA DERIVATIVES AS CANNABINOID TYPE 1 RECEPTOR ALLOSTERIC MODULATORS

Cannabinoid receptor type 1 (CB1R) is an important target to address several pathological conditions like nausea, pain, multiple sclerosis, obesity, nicotine- and alcohol-addiction. Compounds 1-4 and 5-8 were recently reported in literature as analogs of the diaryl ureic CB1R-allosteric modulator PSNCBAM-1. These derivatives showed good results in increasing the binding affinity and in decreasing the receptor functionality of the orthosteric reference compound CP 55,940. In order to identify more potent and selective CB1R-allosteric modulators and to expand the knowledge on the structure-activity relationships for these type of molecules, we designed and synthesized new derivatives combining the structural modifications described in different recently published works,1,2 and performed the biological assessment of three series of compounds: biphenyl derivatives (A), compounds carrying an amine spatial linker with bipyridinyl structure (B) or without the pyrrolidine ring (C). The compounds were subjected to radioligand binding assays (1 nM - 10 μM), using hCB1-CHO cell membrane preparations. Then, through [³⁵S]GTPγS functional assays, we made a selection of compounds based on their inability to significantly alter the cellular response in absence of the orthosteric agonists. These derivatives were furtherly tested in presence of CP 55,940. Compounds 10 and 17 gave the best biological results, behaving as positive allosteric modulators (PAMs) in binding assays and as negative allosteric modulators (NAMs) in functional assays, in line with the parental compound PSNCBAM-1. This outcome seems to suggest that the combination of the biphenyl system and the piperidine ring and, the association of the p-fluorophenyl moiety and the amine spatial linker are significant structural features, which could be taken in account for further developments.