The P2X4 receptor (P2X4R), a ligand‐gated ion channel activated by ATP, plays a critical role in neuroinflammation, chronic pain, and cancer progression, making it a promising therapeutic target. In this study, we explored the design and synthesis of piperazine‐based P2X4R antagonists, building on the structural framework of paroxetine. A series of over 35 compounds were synthesized to investigate structure–activity relationships (SARs) in a Ca²⁺‐flux assay for P2X4R antagonistic activity. Several compounds outperformed paroxetine in terms of antagonistic P2X4R potency. Further studies on absorption, distribution, metabolism, excretion properties revealed that increased lipophilicity often correlated with high plasma protein binding and decreased metabolic stability, particularly in compounds with a naphthalene‐2‐yloxy group. Although promising SARs were observed, further optimization is needed to enhance antagonistic P2X4R receptor activity. This work provides important insights into the development of piperazine‐based P2X4R antagonists and lays the foundation for future therapeutic advancements targeting P2X4R‐related diseases.

2024-04-01·CURRENT MEDICINAL CHEMISTRY

Structure-Activity Relationships and Therapeutic Potential of Purinergic P2X7 Receptor Antagonists

Review

作者: Abate, Carmen ; Leopoldo, Marcello ; Podlewska, Sabina ; Bojarski, Andrzej J. ; Lacivita, Enza ; Ghafir El Idrissi, Imane

Abstract::

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.

2023-06-01·Neuropharmacology

New paradigms in purinergic receptor ligand discovery.

Review

作者: Pradhan, Balaram ; Jacobson, Kenneth A. ; Wen, Zhiwei ; Pramanik, Asmita

The discovery and clinical implementation of modulators of adenosine, P2Y and P2X receptors (comprising nineteen subtypes) have progressed dramatically in ∼50 years since Burnstock's definition of purinergic signaling. Although most clinical trials of selective ligands (agonists and antagonists) of certain purinergic receptors failed, there is a renewed impetus to redirect efforts to new disease conditions and the discovery of more selective or targeted compounds with potentially reduced side effects, such as biased GPCR agonists. The elucidation of new receptor and enzyme structures is steering rational design of potent and selective agonists, antagonists, allosteric modulators and inhibitors. A_2A adenosine receptor (AR) antagonists are being applied to neurodegenerative conditions and cancer immunotherapy. A₃AR agonists have potential for treating chronic inflammation (e.g. psoriasis), stroke and pain, as well as cancer. P2YR modulators are being considered for treating inflammation, metabolic disorders, acute kidney injury, cancer, pain and other conditions, often with an immune mechanism. ADP-activated P2Y₁₂R antagonists are widely used as antithrombotic drugs, while their repurposing toward neuroinflammation is considered. P2X3 antagonists have been in clinical trials for chronic cough. P2X7 antagonists have been in clinical trials for inflammatory diseases and depression (compounds that penetrate the blood-brain barrier). Thus, purinergic signaling is now recognized as an immense regulatory system in the body for rebalancing tissues and organs under stress, which can be adjusted by drug intervention for therapeutic purposes. The lack of success of many previous clinical trials can be overcome given more advanced pharmacokinetic and pharmacodynamic approaches, including structure-based drug design, prodrugs and biased signaling. This article is part of the Special Issue on "Purinergic Signaling: 50 years".

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.

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