Abstract
The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several P2X7 antagonists have been developed, though none of them reached clinical trials for this indication. In this work, we designed and synthesized novel blood-brain barrier (BBB)-permeable derivatives as potential P2X7 antagonists. They comprise purine or xanthine cores linked to an aryl group through different short spacers. Compounds were tested in YO-PRO-1 uptake assays and intracellular calcium dynamics in a human P2X7-expressing HEK293 cell line, two-electrode voltage-clamp recordings in Xenopus laevis oocytes, and in interleukin 1β release assays in mouse peritoneal macrophages. BBB permeability was assessed by parallel artificial membrane permeability assays and P-glycoprotein ATPase activity. Dichloroarylpurinylethanones featured a certain P2X7 blockade, being compound 6 (2-(6-chloro-9H-purin-9-yl)-1-(2,4-dichlorophenyl)ethan-1-one), named ITH15004, the most potent, selective, and BBB-permeable antagonist. Compound 6 can be considered as a first non-nucleotide purine hit for future drug optimizations.
Highlights
Brain disorders affect 1 billion people around the world.1 Neurodegenerative diseases (NDDs) are the most common form of brain disorder and, since they are age-dependent, this results in a high socio-economic burden as the longevity of the global population increases.2 Current available medicines only mitigate some of the symptoms
We explored if lengthening the spacer present in compound 6 affected the pharmacological activity by inserting a propanone instead of an ethanone as the spacer between the purine core and the aryl group (Scheme 3)
The few candidates blocking P2X7 studied in clinical trials have focused on peripheral disorders
Summary
Brain disorders affect 1 billion people around the world. Neurodegenerative diseases (NDDs) are the most common form of brain disorder and, since they are age-dependent, this results in a high socio-economic burden as the longevity of the global population increases. Current available medicines only mitigate some of the symptoms. Brain disorders affect 1 billion people around the world.. Neurodegenerative diseases (NDDs) are the most common form of brain disorder and, since they are age-dependent, this results in a high socio-economic burden as the longevity of the global population increases.. Current available medicines only mitigate some of the symptoms. For this reason, new innovative, more potent, and selective drugs are urgently needed to hinder disease progression. The NDDs, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), feature diverse symptomatology and physiopathology. Recent evidences focus on neuroinflammation as a common central stage in their pathogenesis
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