• GPR55
• GPCR
• agonist
• 3-benzylquinolin-2(1H)-one
• structure-activity relationships
• homology modelling

The GPR55 receptor appears to be a new potential drug target for the treatment of metabolic and neurodegenerative diseases, cancer, osteoporosis and neuropathic pain, even though further studies are required to clarify its role. Potent and selective ligands could therefore represent potential tool compounds to validate this receptor as a pharmacological target, as well as to encourage drug discovery in this field. However, to date, their design remains challenging, given the lack of information about the GPR55 3D structure, and the limited number of ligands reported in the literature, most of which are poorly selective. In addition, data on their pharmacological evaluation appear to be often controversial and strongly influenced by the functional assay performed as well as the cell line used.
Based on 3-benzylcoumarin derivatives previously reported as GPR55 antagonists, a set of novel modulators with a 3-benzylquinolin-2(1H)-one scaffold has been recently developed in the research laboratory where I carried out my thesis work. These compounds resulted to be potent GPR55 agonists and displayed Ki values in the low nanomolar range. Furthermore, the 7-n-butyl-5-methoxy-3-(2-methoxybenzyl)-quinolin-2(1H)-one derivative exhibited complete selectivity over both CBRs. From a homology modelling study of GPR55, it emerged that the ortho-substitution on the 3-benzyl group might be not essential for the receptor interaction. My thesis work consisted in the synthesis of 3-benzyl-7-n-butyl-quinolin-2(1H)-one derivatives in which the benzyl ortho-substituent was removed, in order to assess its effective influence on the interaction within the GPR55 binding pocket and to deepen the preliminary structure-activity relationships (SAR) for this type of molecules. Biological tests to evaluate the GPR55-affinity, selectivity and functional activity of the newly synthesized compounds are currently ongoing at the University of Saskatchewan (Canada).