GPR88 agonists(Acadia Pharmaceuticals)

Nociception, the perception of noxious stimuli, is a critical function for the sensation of pain that protects us from damaging ourselves and helps protect the body following an injury. While pain is important, many people suffer from chronic pain due to a dysregulation of the mechanisms that detect noxious stimuli. G‐protein coupled receptors (GPCRs) are critical regulators of cell function making them frequent targets of therapeutic agents. The recent identification of the neuropeptide PEN as an endogenous ligand for the GPCR, GPR83, opens the possibility of exploring the neurobiological function of this receptor. Recent studies have provided evidence that GPR83 is expressed in a specific ascending spinal tract and that these neurons are highly sensitive to mechanical stimuli. New tools to study GPR83 include small molecule agonists and antagonists. Using these compounds, we have identified that GPR83 agonists blunt morphine antinociception while antagonists enhance morphine antinociception. Since morphine is the most effective therapeutic for pain this suggests that GPR83 is involved in the pain pathway however, it is unknown whether there is a direct impact of GPR83 on nociception. Moreover, the potential of targeting GPR83 to alleviate chronic pain has not been investigated. We have preliminary data suggesting that GPR83 antagonists increase sensitivity to mechanical stimuli while having no impact on thermal stimuli. Our study aims to further characterize GPR83’s role in nociception and to identify whether this receptor has any direct impact on pain itself, using the Complete Freud’s Adjuvant (CFA) model of inflammatory pain.

Although G protein-coupled receptors (GPCRs) are recognized as pivotal drug targets involved in multiple physiological and pathological processes, the majority of GPCRs including orphan GPCRs (oGPCRs) are unexploited. GPR88, a brain-specific oGPCR with particularly robust expression in the striatum, regulates diverse brain and behavioral functions, including cognition, mood, movement control, and reward-based learning, and is thus emerging as a novel drug target for central nervous system disorders including schizophrenia, Parkinson's disease, anxiety, and addiction. Nevertheless, no effective GPR88 synthetic ligands have yet entered into clinical trials, and GPR88 endogenous ligands remain unknown. Despite the recent discovery and early stage study of several GPR88 agonists, such as 2-PCCA, RTI-13951-33, and phenylglycinol derivatives, further research into GPR88 pharmacology, medicinal chemistry, and chemical biology is urgently needed to yield structurally diversified GPR88-specific ligands. Drug-like pharmacological tool function and relevant signaling elucidation will also accelerate the evaluation of this receptor as a viable neurotherapeutic target.