Multicomponent Strategies for GPCR Targeting: Allosteric Modulation of Dopamine Receptor D2 and Development of Potent and Selective CB2R Agonists

Abstract

This PhD thesis focuses on the development of novel, potent, and selective ligands for two therapeutically relevant GPCR targets: the dopamine receptor D2 and the cannabinoid receptor CB2. Different isocyanide-based multicomponent strategies were designed to generate focused small molecule collections that enabled the interrogation of the selected targets, the identification of new lead compounds and the evaluation of the most salient features of the SAR within these series. The first chapter deals with the optimization of novel Melanostatin-inspired allosteric modulators of the D2R. Chapter two documents a systematic MCR-assisted pharmacomodulation process that enabled the dissociation of the promiscuous cannabinomimetic profile of model designer drugs to identify potent, selective, and biased CB2R agonists. The research encompasses molecular design strategies, synthesis, biological evaluation, and structure-activity relationships. Preliminary evidence supporting the attractive antiproliferative activity of selected CB2R agonists in glioblastoma cell lines is also provided.