Abstract by Asmita Manandhar

In recent years, G protein-coupled receptors (GPCRs) have emerged as attractive drug targets due to their significant roles in various physiological processes. This PhD project focuses on the development of ligands for GPR84 and GPR183, both of which are poorly characterized immunomodulatory GPCRs.

GPR84 is a proinflammatory GPCR which is implicated in the pathogenesis of fibrosis and several inflammatory disorders including neuropathic pain, ulcerative colitis, reflux esophagitis, and acute lung injury. Currently, there is a strong need for GPR84 antagonist tool compounds to validate the therapeutic potential of GPR84 inhibition. Manuscript 1 and Manuscript 2 describe the discovery of GPR84 inverse agonists and antagonists from an agonist scaffold and the subsequent structure-activity relationship (SAR) explorations and optimizations leading to the development of a series of GPR84 antagonists with (sub)nanomolar potency. TUG-2653 from this series represents a promising nanomolar potent GPR84 antagonist (IC₅₀ = 2.7 nM) with favorable physicochemical properties, high microsomal stability, and good exposure in mice. Furthermore, Manuscript 3 describes the development of TUG-2713, the first highly potent antagonist fluorescent tracer for GPR84 and its utility as a tool compound to study the binding kinetics of known GPR84 ligands and to assess the receptor expression at a membrane protein level.

GPR183 is a chemotactic GPCR that is known to be activated by endogenous oxysterols, among which 7α,25-dihydroxycholesterol (7α,25-OHC) is the most potent agonist. GPR183/oxysterol signaling modulates the migration of immune cells during humoral immune responses. Thus, the receptor is implicated in numerous inflammatory indications including systemic lupus erythematosus, tuberculosis, multiple sclerosis, neuropathic pain, and rheumatoid arthritis. However, the role of the receptor in these diseases remain largely elusive, and very few agonists as well as antagonists are known. Manuscript 4 describes the development of low nanomolar potent, G protein-biased full agonists for GPR183 as exemplified by TUG-2644 (EC₅₀ = 11 nM, E_max = 91%). These compounds were developed via SAR explorations and optimizations of previously reported partial agonists. Biased agonists such as TUG-2644 could be useful to study the clinical relevance of G protein signaling bias of GPR183.