Hit-to-lead optimization for orphan GPR3 and GPR12 in neurodegenerative diseases

• Applicant: Privatdozent Dr. Steffen Pockes
• Subject Area: Pharmacy ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 533782091

GPR3 and GPR12 belong to the orphan class A G protein-coupled receptors (GPCRs) and together with GPR6 form a separate receptor cluster characterized by strong constitutive stimulation of adenylate cyclase (AC) via Gs proteins and thus by increased levels of the second messenger cAMP. The physiological role of GPR3 and GPR12 is clearly defined by their frequent occurrence in the central nervous system (CNS). They are associated, for example, with neurite growth, neuronal cell survival and anti-apoptotic properties and therefore have enormous potential for the treatment of neurodegeneration. GPR3 mediates the formation of amyloid-β (Aβ) peptides in neurons by interacting with β-arrestin2 and stimulating γ-secretase activity, suggesting therapeutic relevance for targeting Alzheimer's disease (AD) with GPR3 inverse agonists. Furthermore, there are reports linking GPR3 and GPR12 to neuropathic pain, in addition to their involvement in cognitive function. Even though a few ligands have already been described for the receptor cluster, still no endogenous ligands have been found for GPR3/6/12, which means that the receptors are still considered orphan. Particularly in terms of affinity and receptor selectivity, the search for potent, brain-penetrant, drug-like molecules targeting GPR3 and GPR12 is still in its infancy. To effectively advance drug development for both receptors, we have already developed appropriate assay systems to measure receptor binding, receptor conformational changes, as well as functional receptor signaling pathways for GPR3 and GPR12. This set of assay systems will now allow us to further develop our already identified hit and lead structures into selective receptor molecules by medicinal chemistry approaches. To this end, we will use innovative methods such as virtual screening, fragment-based drug discovery, and DNA-encoded libraries to address our target proteins, which have great potential as therapeutic targets in neurodegenerative diseases and could enable restorative treatment.

• DFG Programme: Research Grants