Abstract

The endocannabinoid system consist of two cannabinoids receptors CB1 and CB2, the endogenous ligands such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and enzymes responsible for endogenous ligand synthesis (phospholipase D) and degradation (fatty acid amide hydrolase, FAAH). Extensive preclinical and clinical data support the notion that cannabinoid receptors offer promising approach for the treatment of several pathologies including energy metabolic disorders, chronic inflammation, pain, menthal disfunctions, abuse, cancer, bone loss and liver pathophysiology.
Recently, a research group at University of Sassari described the discovery of a novel series of tricyclic pyrazoles of general structure 1 as ligands for cannabinoid receptors. On the basis of preliminary SAR study three derivatives (1Aa, Ba, Ca Chart 1) were identified as leads. It was envisioned that bioisosteric modification of these structure might offer novel templates that could provide optimized interactions with receptors. Thus, three different scaffolds including tricyclic 1.4-dihydropyrazol-pyrrolizine-, 1,4,5-dihydropyrazolo[4,3-g]indolizine-, and 1,4,5,6- tetrahydropyrazol[3,4-c]pyrrolo[1,2-c]azepine systems (2A-C) were designed.

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