CB1 receptor binding sites for NAM and PAM: A first approach for studying, new n‑butyl‑diphenylcarboxamides as allosteric modulators

The development of cannabinoid receptor type-1 (CB1R) modulators has been implicated in multiple pathophysiological events ranging from memory deficits to neurodegenerative disorders among others, even if their central psychiatric side effects such as depression, anxiety, and suicidal tendencies, have limited their clinical use. Thus, the identification of ligands which selectively act on peripheral CB1Rs, is becoming more interesting. A recent study reported a class of peripheral CB1R selective antagonists, characterized by a 5-aryl substituted nicotinamide core. These derivatives have structural similarities with the biphenyl compounds, endowed with CB2R antagonist activity, previously synthesized by our research group. In this work we combined the pharmacophoric portion of both classes, in order to obtain novel CBR antagonists. Among the synthesized compounds rather unexpectedly two compounds of this series, C7 and C10, did not show the radioligand ([3H]CP55940) displacement on CB1R but increased binding (∼ 150%), suggesting a possible allosteric behavior. Computational studies were performed to investigate the role of these compounds in CB1R modulation. The analysis of their binding poses in two different binding cavities of the CB1R surface, revealed a preferred interaction with the experimental binding site for negative allosteric modulators.