NOP receptor active structure, transducerome, and biased signaling

G protein-coupled receptors (GPCR) control a large number of biological functions via G protein signaling. G proteins are heterotrimers composed of alpha, beta, and gamma subunits. There are 16 genes encoding for alfa subunits, 5 for beta, and 14 for gamma, giving the GPCR a wide spectrum of signaling possibilities. Interestingly, some synthetic GPCR ligands, named biased agonists, stimulate receptor signaling via the selective activation of a specific subset of G proteins. Recent evidence suggests that biased agonists may dissect the beneficial vs. unwanted effects deriving from the stimulation of a given receptor, a concept known as functional selectivity. This observation may lead to the development of biased agonists as more effective/better-tolerated drugs.

The nociceptin/orphanin FQ (N/OFQ) - NOP receptor system modulates different functions in the CNS and periphery, and NOP agonists have therapeutic potential for treating pain, anxiety, locomotor and sleep disorders, drug abuse, and cough. The aim of this project is to explore the molecular basis of functional selectivity at NOP receptors. This will be achieved by developing novel assays to identify and pharmacologically characterize NOP biased agonists, generating and validating the 3D model of the active NOP receptor, and developing structure-based and effector-specific structure-activity studies in order to identify novel compounds showing a large preference for a specific signaling pathway. The experimental techniques and protocols, processes, and concepts that will be developed by a highly collaborative effort of medicinal chemists, structural biologists, molecular biologists, and pharmacologists will be of great value in the future for extending this kind of study to other GPCRs. Thus, this project may greatly contribute to improving our knowledge about functional selectivity and exploiting biased agonism as a strategy for developing a new generation of safer/more effective drugs.