Prolactin-releasing Peptide GPCR Assays
Background of Prolactin-releasing Peptide Receptor (PrRP-R)
PrRP is a specific prolactin-related factor. PrRP may contribute to the control of multiple activities in neuroendocrinology. PrRP functions by binding with G protein-coupled receptor 10 (GPR10). Emerging evidence revealed that PrRP and GPR10 are closely relevant to the processing of nociceptive information in vivo. Additionally, GPR10 plays a crucial role in food intake regulation.
Fig.1 PrRP physiological functions and signaling. (Pražienková, 2019)
Location and Functions of GPR10
GPR10 is widely expressed throughout the brain, especially in brain regions involved in energy homeostasis and the processing of nociceptive signals. The widespread distribution of GPR10 suggests that they have multiple functions not only in the pituitary but also in other tissues. Furthermore, scientists demonstrated an important additional role for the PrRP-GPR10 system in regulating the various effects of opioids. It is worth noting that GPR10 is emerging as a potential pharmacological target for the clinical treatment of pain and addiction disorders.
Pathways of GPR10
GPR10 is a Gi/o-coupled receptor, which activates the extracellular ERK signaling cascade. In addition, many other pathways are also related to the regulation of PrRP and GPR10 signaling.
| Receptor | Gene | Mechanism | Agonists | Antagonists |
| GPR10 Receptor | PRLHR |
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Published Data
| Paper Title | Design of a Long-Acting and Selective MEG-Fatty Acid Stapled Prolactin-Releasing Peptide Analog |
| Journal | ACS medicinal chemistry letters |
| Published | 2019 |
| Abstract | As a new member of the RFamide family secreted by the hypothalamus, PrRP shows great potential for the treatment of obesity by activating GPR10 to reduce food intake and body weight in rodent models. This article described a long-acting PrRP designed using a novel polyglycol-fatty acid (MEG-FA) binding platform. A series of PrRP analogs with enhanced serum stability and in vivo half-life were synthesized by conjugating serum albumin-binding fatty acids to covalent side-chain staples. The lead compound 18-S4 showed considerable in vitro potency and selectivity for GPR10. The compound not only improves serum stability but also prolongs half-life in mice. Therefore, 18-S4 represents an attractive long-acting PrRP analog that can be used for further evaluation in the chronic obesity setting. |
| Result |
This article developed a promising long-acting PrRP analog through a strategy that combines helical stability with the MEG-FA serum protein binding motif. Notably, peptide 18-S4 not only retained activity against GPR10 but also had good selectivity for NPFF2R (neuropeptide FF receptor 2). Furthermore, 18-S4 has higher plasma stability and prolonged half-life in vivo compared to PrRP31. Most importantly, in DIO mice, 18-S4 showed a weight loss effect compared to vehicle treatment, demonstrating a potent anorexic effect. Therefore, 18-S4 offers a potential strategy for obesity research and warrants further evaluation in chronic obesity and metabolic disease models.
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Fig.2 In vitro plasma stability of PrRP31, 18-S2, and 18-S4. (Pflimlin, 2019)
References
- Pražienková,s V.; et al. Prolactin-releasing peptide: physiological and pharmacological properties. International journal of molecular sciences. 2019; 20(21): 5297.
- Pflimlin, E.; et al. Design of a Long-Acting and Selective MEG-Fatty Acid Stapled Prolactin-Releasing Peptide Analog. ACS medicinal chemistry letters. 2019; 10(8): 1166-1172.
