RC-3095 / EMD Serono - LARVOL DELTA

Imperatorin activates TRPV1/GRPR pathway to induce scratching behaviors in mice. (PubMed, Neuropharmacology) - "IMP-induced scratching could be mitigated by an intrathecal injection of the GRPR antagonist RC3095, and the IMP-evoked increase in c-Fos expression in GRPR+ neurons in the spinal cord was attenuated by TRPV1 deficiency. These findings suggest that IMP could trigger itch-related responses, at least partially, via the activation of TRPV1+ neurons in the DRG and subsequently the GRPR+ neurons in the spinal cord. IMP may therefore serve as an efficient nonhistaminergic model of acute itch to screen of potential anti-pruritus agents."

Journal • Preclinical • Dermatology • Pruritus • FOS • TRPV1

Astrocytic LCN2 drives uremic pruritus and morphine-induced pruritus via the GRP/GRPR pathway. (PubMed, Clin Exp Nephrol) - "LCN2 mediates pruritus by promoting GRP/GRPR signaling, astrocyte activation, and neuroinflammation, making it a potential therapeutic target for CKD-related and opioid-induced pruritus."

Journal • Chronic Kidney Disease • Dermatology • Inflammation • Pruritus • Renal Disease

Peptidergic Systems and Neuroblastoma. (PubMed, Int J Mol Sci) - "Although the data regarding the involvement of the peptidergic systems in neuroblastoma are, in many cases, fragmentary or very scarce for a particular peptidergic system, taken together, they are quite promising with respect to potentiating and developing this research line with the aim of developing new therapeutic strategies to treat neuroblastoma in the future. Peptidergic systems are potential and promising targets for the diagnosis and treatment of neuroblastoma."

Journal • Review • Neuroblastoma • Oncology • Solid Tumor

Characterization and targeting of the endosomal signaling of the gastrin releasing peptide receptor in pruritus. (PubMed, bioRxiv) - "Intrathecal injection of RC-3095 loaded nanoparticles blocked chloroquine induced scratching behavior in mice. Thus, intracellular GRPR drives itch sensation and targeted inhibition of intracellular GRPR signaling is a more effective strategy to treat pruritus."

Journal • Dermatology • Pruritus • GRP-10

Gastrin-releasing peptide receptor antagonist RC-3095 inhibits Porphyromonas gingivalis lipopolysaccharide-accelerated atherosclerosis by suppressing inflammatory responses in endothelial cells and macrophages. (PubMed, Inflamm Res) - "RC-3095 can alleviate P. gingivalis LPS-induced endothelial inflammation, macrophage polarization, and atherosclerosis progression, suggesting its potential as a therapeutic approach for periodontal pathogen-associated atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • APOE • GRP-10 • ICAM1 • VCAM1

The Characterization and Targeting of Endosomal Signaling of GRPR in Itch. (IASP 2024) - "Intrathecal injections of endosomal inhibitors, RC3095, empty MSN or MSN loaded with RC3095 (MSN-RC3095) were followed by intradermal injections of chloroquine (CQ). GRPR internalizes to the endosomal compartment following activation by GRP. GRPR is able to recruit G proteins to the endosome where GRPR induces cytosolic and nuclear ERK signaling. These results demonstrate a critical role for GRPR endosomal signaling in modulating cellular responses."

Dermatology • Pruritus • GPRC6A • GRP-10 • RAB5A

Gastrin-Releasing Peptide/Gastrin-Releasing Peptide Receptor Participation in Itch Sensation Signaling in the Spinal Cord of Uremic Pruritus Mice. (PubMed, Altern Ther Health Med) - "Y group scratching times were higher than normal and sham groups, increasing after intrathecal gastrin-releasing peptide but decreasing after RC-3095 injection. The gastrin-releasing peptide/gastrin-releasing peptide receptor signaling pathway is involved in the development of uremic pruritus."

Journal • Preclinical • Dermatology • Pruritus • Renal Disease • GRP-10

Intrathecal Administration Of Morphine Induces Itching Behavior, Which 5ht3 Receptor Antagonists Can Ameliorate. (ASA 2023) - "To assess the serotonergic involvement, the same experiment was performed against the pretreatment of serotonin-depleted toxin para-chlorophenylalanine (PCPA, 150 mg/kg for four days) and 5HT3 receptor antagonist ondansetron (OND: 0.05, 0.1, 0.5 mg/kg i.t. administration 1 hour before morphine administration)...However, GRPR antagonist RC3095 (1 nmol) co-administered with morphine did not suppress SBL behavior (morphine 30 nmol: 47.2 ± 5.2 sec, morphine+ RC3095: 64.1 ± 5.9 sec, p=0.04) suggested that contribution of GRPR activation to morphine-induced itch was small... Intrathecal morphine administration induced itch related behavior in a dose dependent manner. Also, intrathecal morphine induced upregulation of GRP and serotonin in spinal dorsal horn. However, it was suggested that serotonin may have a higher contribution than GRP to morphine-induced itching behavior."

Addiction (Opioid and Alcohol) • Pruritus • GRP-10

Oral presentation from selected ESDR poster abstracts: GRP induces prometastatic signaling in melanoma (ESDR 2022) - "Targeting GRPR with the GRPR antagonist, RC-3095, drastically decreases the formation of melanoma metastases after injection of cells into the tail vein of mice. Therefore, our study highlights the importance of the newly discovered E-cad/GRPR axis in melanoma progression. Moreover, our results propose GRPR targeting as a new therapeutic option in treating melanoma metastases."

Melanoma • Oncology • Solid Tumor • CDH1 • GRP-10 • YAP1

GRPR is an effective target for melanoma (ESDR 2022) - "Targeting GRPR with the GRPR antagonist, RC-3095, drastically decreases the formation of melanoma metastases after injection of cells into the tail vein of mice. Therefore, our study highlights the importance of the newly discovered E-cad/GRPR axis in melanoma progression. Moreover, our results propose GRPR targeting as a new therapeutic option in treating melanoma metastases."

Melanoma • Oncology • Solid Tumor • CDH1 • GRP-10 • YAP1

Functional roles of neuromedin B and gastrin-releasing peptide in regulating itch and pain in the spinal cord of non-human primates. (PubMed, Biochem Pharmacol) - "GRP- and NMB-elicited scratching responses were attenuated by GRPR (RC-3095) and NMBR (PD168368) antagonists, respectively...Spinal NMB-NMBR system plays a minimal functional role in the neurotransmission of itch and pain in primates. Unlike the functional significance of the GRP-GRPR system in itch, drugs targeting the spinal NMB-NMBR system may not effectively alleviate non-NMBR-mediated itch."

Journal • Dermatology • Immunology • Pain • Pruritus • GRP-10

Blocking GRP/GRP-R signaling decreases expression of androgen receptor splice variants and inhibits tumor growth in castration-resistant prostate cancer. (PubMed, Transl Oncol) - "Our studies show that blocking GRP/GRP-R signaling by targeting GRP-R using RC-3095, a selective GRP-R antagonist, efficiently inhibits NF-κB activity and ARVs (AR-V7) expression in CRPC and therapy-induced NEPC (tNEPC) cells. In addition, blocking of GRP/GRP-R signaling by targeting GRP-R can sensitize CRPC cells to anti-androgen treatment (such as MDV3100). Further, preclinical animal studies indicate combination of GRP-R antagonist (targeting ARVs) with anti-androgen (targeting AR-FL) is sufficient to inhibit CRPC and tNEPC tumor growth."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • GRP-10

Inhibition of Gastrin-Releasing Peptide Attenuates Phosphate-Induced Vascular Calcification. (PubMed, Cells) - "Moreover, the treatment with RC-3095 effectively ameliorated phosphate-induced calcium deposition in rat aortas ex vivo and aortas of chronic kidney disease in mice in vivo. Therefore, the regulation of the GRP-GRP receptor axis may be a potential strategy for treatment of diseases associated with excessive vascular calcification."

Journal • Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease • GRP-10

A Critical Role for the CXCL3/CXCL5/CXCR2 Neutrophilic Chemotactic Axis in the Regulation of Type 2 Responses in a Model of Rhinoviral-Induced Asthma Exacerbation. (PubMed, J Immunol) - "Similar results were obtained by employing RC-3095, which has been shown to bind to CXCR2, or by depletion of neutrophils. Our data demonstrate that CXCL3 and CXCL5 may be critical in the perpetuation of RV-induced exacerbation of asthma through the recruitment of CXCR2-positive neutrophils and by promoting type 2 inflammation. Targeting the CXCL3/CXCL5/CXCR2 axis may provide a new therapeutic approach to attenuating RV-induced exacerbations of asthma."

Journal • Asthma • Immunology • Inflammation • Respiratory Diseases • CCL11 • CCL4 • CXCL5 • CXCR2 • IL13 • IL5

Phase shifts to light are altered by antagonists to neuropeptide receptors. (PubMed) - "These results indicate that photic phase shifting requires participation of either VIP or GRP, and only when signaling in both pathways is inhibited are phase shifts to light impaired. Additionally, the unexpected potentiation of light-induced phase shifts by RC-3095 should be investigated further for potential chronobiotic applications."

Journal • Biosimilar • Ophthalmology

GRP receptor and AMPA receptor cooperatively regulate itch-responsive neurons in the spinal dorsal horn. (PubMed, Neuropharmacology) - "In mice, peripherally elicited histaminergic and non-histaminergic itch was prevented by intrathecal (i.t.) administration of the AMPAR antagonist NBQX, which was consistent with the fact that firing of GRPR neurons in SDH under histaminergic and non-histaminergic itch was completely blocked by NBQX, but not by the GRPR antagonist RC-3095...Altogether, these findings demonstrate that GRP and glutamate cooperatively regulate GRPR AMPAR neurons in SDH, mediating itch sensation. GRP-GRPR and the glutamate-AMPAR system may play pivotal roles in the spinal transmission of itch in rodents and nonhuman primates."

Journal • GRP-10