Pyrrole derivatives targeting the Endocannabinoid System (ECS) in Prostate Cancer Cells

Cannabinoid receptors (CB) are integral components of the endocannabinoid system (ECS), including at least two receptor types, cannabinoid receptor type-1 (CB1) and cannabinoid receptor type-2 (CB2) belong to the large family of G-protein-coupled receptors.  Initially discovered in the brain, CB1 receptors are distributed in peripheral nerve terminals and extra-neural sites such as the testis, eye, vascular endothelium, and spleen. In contrast, CB2 receptors are primarily localized in peripheral nerve tissues, immune organs, and several other organs including the heart, lungs, and pancreas 1 . Structural differences between CB1 and CB2 receptors are notable, with CB1 composed of 472 amino acids and CB2 of 360 amino acids. Despite these disparities, both receptors share moderate sequence homology, particularly within the transmembrane domains (68%), which are crucial for cannabinoid binding 2 . Understanding the distinct distributions and structural features of CB1 and CB2 receptors is essential for elucidating their diverse physiological functions and developing targeted therapeutic interventions. ECS has been proposed as a possible target for the treatment of prostate cancer, and research suggests that targeting this system could be a promising avenue for treatment. In fact, results from preclinical studies have highlighted altered levels of endocannabinoids in patients’ plasma and identified a correlation between high CB1/CB2 receptor expression and a poor prognosis 3 . Considering the role played by the ECS in prostate cancer, we designed and synthesized a small set of 2,3,4-trisubstituted pyrrole derivatives to study their ability to interact with both CB1 and CB2 receptors and to evaluate any effect on apoptotic processes in cellular models of prostate cancer, such as PC3, DU145(androgen-independent human prostate cancer cells) and LNCaP (androgen-dependent human prostate cancer cell line) that naturally express the endocannabinoid system. The data coming from the biochemical assays will be shown and discussed.