Development of Novel Neuropeptide B/W Receptor 1 Agonists

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Abstract G protein-coupled receptors (GPCRs) are a major family of targets for drug development; however, only a small number of GPCRs have successfully provided drugs on the market and many remain understudied for therapeutic applications. A lack of suitable tool compounds is a major obstacle to understand physiological functions of these understudied GPCRs. Neuropeptide B/W Receptor 1 (NPBWR1) has been suggested to hold great potential for several therapeutic applications, particularly for pain treatment based on its overexpression in patients' samples and in vivo studies using endogenous neuropeptides. Due to their metabolic instability and poor membrane permeability, these native neuropeptides require central administration, making them unsuitable for therapeutics development. Till date, no small molecule agonists have been discovered yet. Recognizing the unmet need to develop more stable and druglike tool compounds to facilitate research on this promising target, we propose to develop NPBWR1 agonists using a two-pronged approach, peptidomimetic design and repurposing opioid receptor ligands.