Purinergic receptor expression in neuronal, bladder smooth muscle and urothelial cells: characterization and inhibition by low molecular weight antagonists.
Doctoral thesis, UCL (University College London).
P2 purinoceptors comprise ionotropic (P2X) and metabotropic (P2Y) receptor families, responsive to nucleotide ligands and diversely distributed on virtually every mammalian cell. Most cells and tissues co-express multiple subtypes of purinoceptor; thus, unraveling the functional role – and pharmacological potential – of any subtype is a complex task. Additionally limiting is the paucity of potent, selective antagonists, particularly those with suitable physicochemical and pharmacokinetic properties for animals models and clinical development. These studies address questions initially debated >10 years ago, following the successful cloning of purinoceptor families. First, given the large, polyanionic or nucleotide chemical probes available for pharmacology, are these receptors medicinally tractable? Secondly, given the admixture of purinoceptor expression in mammalian cells, would selective interference impact pathophysiology and disease burden; or would redundancy dominate? Through the current investigations some answers can be offered. First, a resounding “yes”, second, a more equivocal “possibly”. Importantly, in addressing these queries, our investigations – and others - have furnished both important data on biological relevance of P2 subtype expression and function, as well as excellent chemical and biological tools for future investigators, so that more answers can be found. Meanwhile, the pharmacological characteristics of two novel prototype antagonists have been detailed: for P2X1 (RO-1) and P2X3-containing receptors (RO-4). Additionally, the potential value of these compounds for the study of P2X signaling in vitro and in vivo, as well as templates for candidate medicines with a wide variety of potential therapeutic uses are demonstrated. It has also been possible to elucidate the potential of selective interference in certain target tissues – urological and sensory – and increasing the apparent therapeutic potential. We can indeed conclude that P2X channels of focus in this work, P2X1, P2X3 and P2X2/3, are druggable; the true therapeutic value of antagonists of these channels is awaited.
|Title:||Purinergic receptor expression in neuronal, bladder smooth muscle and urothelial cells: characterization and inhibition by low molecular weight antagonists|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Neuroscience, Physiology and Pharmacology|
Archive Staff Only