作者: Rashed, Mahmoud ; Boshta, Nader M. ; Namasivayam, Vigneshwaran ; Voss, Jan H. ; Tian, Maoqun ; Lewash, Michael ; Liedtke, Andy J. ; Hockemeyer, Jörg ; Junker, Anna ; Müller, Christa E. ; Sarkar, Soumya ; Kostenis, Evi ; Köse, Meryem ; Pegurier, Cécile ; Stößel, Anne ; Mahal, Ahmed ; Merten, Nicole

The G protein-coupled receptor 17 (GPR17) is an orphan receptor involved in inflammatory diseases. GPR17 antagonists have been proposed for the treatment of multiple sclerosis due to their potential to induce remyelination. Potent, selective antagonists are required to enable target validation. In the present study, we describe the discovery of a novel class of GPR17 antagonists based on an anthranilic acid scaffold. The compounds' potencies were evaluated in calcium mobilization and radioligand binding assays, and structure-activity relationships were analyzed. Selected antagonists were additionally studied in cAMP and G protein activation assays. The most potent antagonists were 5-methoxy-2-(5-(3'-methoxy-[1,1'-biphenyl]-2-yl)furan-2-carboxamido)benzoic acid (52, PSB-22269, K_i 8.91 nM) and its 3'-trifluoromethyl analog (54, PSB-24040, K_i 83.2 nM). Receptor-ligand docking studies revealed that the compounds' binding site is characterized by positively charged arginine residues and a lipophilic pocket. These findings yield valuable insights into this poorly characterized receptor providing a basis for future drug development.

2022-05-01·FASEB JOURNAL

Uncovering the role of neuropeptide receptor GPR83 in nociception

Article

作者: Hanlon, Jack P. ; Fakira, Amanda K. ; Young, Ryan E. ; Devi, Lakshmi A.

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.

项与 GPR17拮抗剂(罗氏) 相关的新闻（医药）

2024-09-18

·Business Wire

Myrobalan to present GPR17 antagonist preclinical data at ECTRIMS 2024

MEDFORD, Mass.--( BUSINESS WIRE )--Myrobalan Therapeutics, a biotechnology company developing novel oral small-molecule therapies to repair damage and restore brain function in high-unmet need central nervous system (CNS) conditions, today announced data demonstrating that their small molecule G protein-coupled receptor 17 (GPR17) antagonists show a biological effect in a number of in vitro and in vivo preclinical models. The data were presented in a poster at the 40 th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), taking place in Copenhagen, Denmark, September 17–20, 2024. The ECTRIMS data demonstrate an effect by Myrobalan’s GPR17 antagonists on oligodendrocyte maturation, a requirement for remyelination, compared to controls in human induced pluripotent stem cell-derived oligodendrocytes and in multiple mouse models of demyelination. Enhanced remyelination was also observed after treatment with a GPR17-antagonist compound in a mouse model. “ Patients with MS could benefit greatly from treatments that have potential to reverse the course of their disease by repairing the myelin damage that drives it. Currently available disease-modifying treatments address inflammatory processes, but are unable to repair damage to myelin, which is a critical mechanism of progression,” said Dr. Jing Wang, Chief Executive Officer of Myrobalan Therapeutics. “ The data from our GPR17 program demonstrate regenerative activity in both human iPSC and animal models, including direct evidence of remyelination in the brain, which gives us confidence to rapidly advance this program into the clinic.” Myrobalan Therapeutics is currently advancing its oral small molecule GPR17 antagonist program to demonstrate that it can safely promote remyelination as a proof of mechanism in upcoming clinical trials. Compounds generated to date have been shown to be potent, highly selective, and brain-penetrant in preclinical testing. About Myrobalan Therapeutics Myrobalan Therapeutics is a preclinical stage biotechnology company headquartered in Medford, Massachusetts, with a focus on developing oral neurorestorative therapies aimed at reversing key pathologies underlying brain dysfunctions and CNS conditions. Myrobalan applies deep knowledge of neurological processes such as demyelination and neuroinflammation, and innovative drug discovery tools, to create highly selective and brain-penetrant therapeutic candidates that are uniquely positioned for treating CNS conditions with significant unmet medical need. Myrobalan’s pipeline of novel remyelination and anti-neuroinflammation programs are being advanced with the strategic support of renowned institutional co-founders. Myrobalan is committed to a transformed future in which patients with degenerative CNS conditions can access safe and effective medicines offering restorative potential. For more information on Myrobalan Therapeutics, visit our website at myrotx.com .

100 项与 GPR17拮抗剂(罗氏) 相关的药物交易

登录后查看更多信息