The purinergic P2X7 receptor (P2X7R), an ATP-gated non-selective cation channel, has emerged as a gatekeeper of inflammation that controls the release of proinflammatory cytokines. As a key player in initiating the inflammatory signaling cascade, the P2X7 receptor is currently under intense scrutiny as a target for the treatment of different pathologies, including chronic inflammatory disorders (rheumatoid arthritis and osteoarthritis), chronic neuropathic pain, mood disorders (depression and anxiety), neurodegenerative diseases, ischemia, cancer (leukemia), and many others. For these reasons, pharmaceutical companies have invested in discovering compounds able to modulate the P2X7R and filed many patent applications. This review article presents an account of P2X7R structure, function, and tissue distribution, emphasizing its role in inflammation. Next, we illustrate the different chemical classes of non-competitive P2X7R antagonists reported by highlighting their properties and qualities as clinical candidates for treating inflammatory disorders and neurodegenerative diseases. We also discuss the efforts to develop effective Positron Emission Tomography (PET) radioligands to progress the understanding of the pathomechanisms of neurodegenerative disorders, to provide evidence of drug-target engagement, and to assist clinical dose selection for novel drug therapies.

2022-01-01·Methods in molecular biology (Clifton, N.J.)

Agonists, Antagonists, and Modulators of P2X7 Receptors.

Article

作者: Namasivayam, Vigneshwaran ; Müller, Christa E

The P2X7 receptor has been proposed as a novel drug target for different types of diseases associated with inflammation, including brain diseases, peripheral inflammation, and cancers. Structurally diverse P2X7 receptor antagonists, mainly negative allosteric modulators (NAMs), have been developed in recent years, and several P2X7 receptor antagonists are currently evaluated in clinical trials. The P2X7 receptor requires high micro- to even millimolar ATP concentrations to be activated. Selective agonists for the P2X7 receptor are not available. Positive allosteric modulators (PAMs) have been described, but PAMs with high potency and selectivity are still lacking. This chapter discusses medicinal chemistry approaches toward the development of P2X7 receptor modulators and presents a selection of recommended tool compounds for studying P2X7 receptors in humans and rodents.

2021-05-01·Biochemical pharmacology2区 · 医学

Medicinal chemistry of P2 and adenosine receptors: Common scaffolds adapted for multiple targets

2区 · 医学

Review

作者: Müller, Christa E ; Jacobson, Kenneth A ; IJzerman, Adriaan P

Prof. Geoffrey Burnstock originated the concept of purinergic signaling. He demonstrated the interactions and biological roles of ionotropic P2X and metabotropic P2Y receptors. This review paper traces the historical origins of many currently used antagonists and agonists for P2 receptors, as well as adenosine receptors, in early attempts to identify ligands for these receptors - prior to the use of chemical libraries for screening. Rather than presenting a general review of current purinergic ligands, we focus on common chemical scaffolds (privileged scaffolds) that can be adapted for multiple receptor targets. By carefully analyzing the structure activity relationships, one can direct the selectivity of these scaffolds toward different receptor subtypes. For example, the weak and non-selective P2 antagonist reactive blue 2 (RB-2) was derivatized using combinatorial synthetic approaches, leading to the identification of selective P2Y₂, P2Y₄, P2Y₁₂ or P2X2 receptor antagonists. A P2X4 antagonist NC-2600 is in a clinical trial, and A₃ adenosine agonists show promise, for chronic pain. P2X7 antagonists have been in clinical trials for depression (JNJ-54175446), inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, inflammatory pain and chronic obstructive pulmonary disease (COPD). P2X3 antagonists are in clinical trials for chronic cough, and an antagonist named after Burnstock, gefapixant, is expected to be the first P2X3 antagonist filed for approval. We are seeing that the vision of Prof. Burnstock to use purinergic signaling modulators, most recently at P2XRs, for treating disease is coming to fruition.

项与 P2X7 receptor antagonists(Chengdu University) 相关的新闻（医药）

2023-07-25

·Pharmaceutical Technology

Golgi and Breye partner to develop P2X7 receptor antagonist programme

Diabetic retinopathy is one of the main reasons for blindness among working-age adults. Credit: Alexander Grey from Pixabay. Golgi Neurosciences has joined forces with Breye Therapeutics for the development of a P2X7 receptor antagonist programme. The receptor, a vital inflammation switch, is an adenosine triphosphate (ATP) gated ion channel found in several cell types. Recommended Reports Reports Beta 2 Adrenergic Receptor (Beta 2 Adrenoreceptor or ADRB2) Drugs in Development by Therapy Areas... GlobalData Reports D2 Dopamine Receptor (Dopamine D2 Receptor or DRD2) Drugs in Development by Therapy Areas and Ind... GlobalData View all Companies Intelligence Breye Therapeutics ApS View all The oral P2X7 receptor antagonists offer a new treatment approach for both early-stage diabetic retinopathy (DR) and dry age-related macular degeneration (dry AMD). Golgi Neurosciences managing director Chiara Liberati said: “With leading experts on the Scientific Advisory Board, Breye is led by a strong and seasoned Management team, supported by a highly-regarded syndicate of investors, making Breye the ideal partner to facilitate the next steps in advancing our P2X7 receptor antagonist program towards developing innovative approaches for retinal disorders.” DR impacts around 30% of individuals with diabetes and is one of the main reasons for blindness among working-age adults. AMD is a significant factor contributing to the loss of vision, especially among individuals aged 60 years and older. Breye Therapeutics CEO Ulrik Mouritzen said: “The Golgi incubator has fantastic expertise in neurosciences, and we are pleased to collaborate to advance the P2X7 receptor antagonist programme for retinal disorders, where there is a large unmet medical need for more effective and less burdensome therapies.” Based in Milan, Italy, Golgi is involved in the discovery and development of small molecule-based therapies for neurodegenerative diseases. Breye is focused on the development of novel, oral ophthalmology drugs for DR and AMD.