NPBWR1

NPBWR1 is a class A GPCR - formerly designated GPR7 - that mediates the actions of neuropeptides B and W in the hypothalamus, amygdala, and HPA axis, where it modulates energy balance, stress responses, and pain. NPBWR1 is phylogenetically closest to the opioid receptor family (its gene is adjacent to OPRK1 on chromosome 8) and, like opioid receptors, couples primarily to Gi/o to suppress cAMP and modulate neuronal excitability. The system is underexplored pharmacologically - no selective NPBWR1 agonist or antagonist has reached clinical trials - but rodent knockout and pharmacological data implicate it in obesity, HPA dysregulation, and inflammatory pain, making it a tractable target for peptide scaffold development.

NPBWR1 (chromosome 8q11.23, 328 aa, intronless coding sequence) is a Gi/o-coupled class A GPCR. Its endogenous ligands are neuropeptide B (NPB-23 and NPB-29) and neuropeptide W (NPW-23 and NPW-30). NPB is unique among neuropeptides in undergoing post-translational bromination at its N-terminal Trp1, which enhances NPBWR1 selectivity over NPBWR2. NPB-29 binds NPBWR1 with Ki ~0.3 nM; NPW binds both NPBWR1 and NPBWR2 equipotently (~0.5–1 nM). The N-terminal Trp is essential - its deletion abolishes activity entirely. Signaling: Gi/o → adenylyl cyclase inhibition → cAMP suppression; context-dependent Gq/PLC/Ca²⁺ also observed. Key binding residues from homology modeling include Trp102 (ECL1), Val113^{3.29} (TM3), Gln281 (ECL3), and Ala274^{6.58} (TM6). NPBWR1 is expressed in hypothalamic arcuate and paraventricular nuclei, amygdala, hippocampus, and periaqueductal gray centrally; peripherally in adrenal glands, testis, and lung. NPBWR2 is absent in rodents but present in humans and pigs - this species gap complicates translational studies. Central NPW administration suppresses food intake; NPBWR1 knockout mice develop late-onset obesity linked to altered leptin signaling and energy partitioning. NPW activates hypothalamic orexin neurons to drive arousal and stress responses; NPB/NPW central administration elevates corticosterone and prolactin.

No NPBWR1-selective compound is approved or in clinical trials. Research tools: NPB-23 and NPW-23 are commercially available as pharmacological probes. Non-selective opioid-like antagonists show partial cross-reactivity, but no clean NPBWR1 tool compound analogous to naloxone exists. For peptide research, the tractable recipes are: NPB N-terminal brominated Trp1 analogs with C-terminal truncations to define the minimal pharmacophore for NPBWR1 selectivity over NPBWR2; Aib or D-amino acid substitutions at positions 2–5 of NPB-23 for protease resistance while preserving NPBWR1 subnanomolar affinity; cyclic NPW analogs constrained by lactam bridges to lock the bioactive conformation identified by computational docking in the TM3/ECL3 pocket; and truncated NPW C-terminal fragments (the Trp-amide terminus drives key contacts) as scaffolds for biased Gi-only agonists that suppress HPA activation without the β-arrestin-mediated desensitization that limits sustained use.