PSNCBAM-1 analogs: Structural evolutions and allosteric properties at cannabinoid CB1 receptor

• Published in: European journal of medicinal chemistry 2020-10, Vol.203, p.112606, Article 112606
• Main Authors: Meini, Serena, Gado, Francesca, Stevenson, Lesley A., Digiacomo, Maria, Saba, Alessandro, Codini, Simone, Macchia, Marco, Pertwee, Roger G., Bertini, Simone, Manera, Clementina
• Format: Article
• Language: English
• Subjects: Allosteric modulator; Allosteric Regulation - drug effects; CB1 receptors; Diaryl urea; Dose-Response Relationship, Drug; Endocannabinoid system; GTP; Humans; Ligands; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacology; PSNCBAM-1; Pyridines - chemistry; Pyridines - pharmacology; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - chemistry; Receptor, Cannabinoid, CB1 - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112606

Allosteric modulation of the CB1Rs could represent an alternative strategy for the treatment of diseases in which these receptors are involved, without the undesirable effects associated with their orthosteric stimulation. PSNCBAM-1 is a reference diaryl urea derivative that positively affects the binding affinity of orthosteric ligands (PAM) and negatively affects the functional activity of orthosteric ligands (NAM) at CB1Rs. In this work we reported the design, synthesis and biological evaluation of three different series of compounds, derived from structural modifications of PSNCBAM-1 and its analogs reported in the recent literature. Almost all the new compounds increased the percentage of binding affinity of CP55940 at CB1Rs, showing a PAM profile. When tested alone in the [35S]GTPγS functional assay, only a few derivatives lacked detectable activity, so were tested in the same functional assay in the presence of CP55940. Among these, compounds 11 and 18 proved to be functional NAMs at CB1Rs, dampening the orthosteric agonist-induced receptor functionality by approximately 30%. The structural features presented in this work provide new CB1R-allosteric modulators (with a profile similar to the reference compound PSNCBAM-1) and an extension of the structure-activity relationships for this type of molecule at CB1Rs. [Display omitted] •We synthesized and evaluated novel PSNCBAM-1 analogs as CB1R allosteric modulators.•Some compounds acted as PAMs for the binding of orthosteric agonist CP55940 at CB1Rs.•Compounds 11 and 18 proved to be functional NAMs at CB1Rs.•New insights for SAR of diaryl urea derivatives at CB1Rs were provided.