Synthesis and biological evaluation of novel cannabinoid receptors allosteric modulators

The endocannabinoid system (ECS) is a complex biochemical system, ubiquitously distributed in the organism and constituted by specific receptors, (CB1R and CB2R), endogenous ligands (i.e. endocannabinoids) and all the enzymes responsible for their synthesis, transport and degradation. ECS is considered a promising therapeutic target for the treatment of several diseases, due to its involvement in different biochemical processes such as metabolism and energy balance, pain transmission and inflammation, neurodegeneration and many others. In spite of the development of a wide number of cannabinoid receptors orthosteric ligands, this class of compounds has a very limited use in therapy, because of the elicitation of severe side effects, like psychotropic effects, cognitive impairments, mood alterations and suicidal tendencies. In comparison with the use of cannabinoid receptors orthosteric ligands, allosteric modulation is related to several pharmacological benefits such as a “fine tuning” of the signaling, saturability of the effect and an increased subtype selectivity. Given these premises, which label allosteric modulation as a potential safer therapeutic approach, in this thesis I reported the design, synthesis and biological evaluation of new compounds, with the aim to deepen the knowledge of the structural requirements of CBRs allosteric binding sites and to identify novel cannabinoid receptors modulators with higher potency and subtype selectivity. My thesis manuscript describes two different topics: - Design, synthesis and pharmacological evaluation of CB1R selective allosteric modulators with diaryl urea structure. Starting from the well-known CB1R selective allosteric modulator PSNCBAM-1, I designed, synthesized and biologically evaluated new derivatives, obtained combining the most recent promising structural features reported in literature. - Design, synthesis and pharmacological evaluation of CB2R selective allosteric modulators with pyridine-2-one structure. Starting from the first synthetic CB2R selective allosteric modulator C2, I designed, synthesized and biologically evaluated five different series of derivatives, differently modifying the substituents of the central core.