Novel P2X7 receptor antagonists ease the pain.
In recent months, a series of chemically diverse antagonists has been identified for the ATP-gated P2X(7) receptor. In particular, two classes of highly-selective competitive P2X(7) antagonists have been developed by Michael Jarvis and his colleagues at Abbott Laboratories. These di-substituted tetrazole and cyanoguanidine derivatives are outstanding for a number of reasons (not least their stability, selectivity, potency and, of course, reversibility); most exciting is their near equal potency at human and rodent P2X(7) isoforms. Armed with drugs such as A740003 and newer A438079, Jarvis and colleagues have explored the role of P2X(7) receptors in the onset and persistence of chronic pain in animal models. Their findings - and applicability to the human condition - are reviewed in this current issue of British Journal of Pharmacology. This accompanying Commentary describes the progress made by Jarvis and others in developing novel P2X(7) antagonists for pain relief.
King
B F
BF
University College London, Department of Physiology (Hampstead Campus), London, UK. b.king@medsch.ucl.ac.uk
D000081:Acetamides / Q000627:therapeutic use*; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D008274:Magnesium / Q000494:pharmacology; D009411:Nerve Endings / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects; D010146:Pain / Q000188:drug therapy*; D010636:Phenols / Q000627:therapeutic use*; D011083:Polycyclic Compounds / Q000627:therapeutic use*; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles / Q000627:therapeutic use*
C515928:(N-(1-(((cyanoimino)(5-quinolinylamino) methyl) amino)-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide); C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; C470346:A-317491; D000081:Acetamides; D018712:Analgesics, Non-Narcotic; C546468:P2RX7 protein, human; D010636:Phenols; D011083:Polycyclic Compounds; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines; D011804:Quinolines; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D008274:Magnesium