Nucleotides such as ATP, ADP, UTP and UDP are important extracellular signalling molecules, that activate two classes of cell membrane receptors: G protein-coupled P2Y receptors (subtypes: P2Y1,2,4,6,11,12,13,14) and ligand-gated ion channels termed P2X receptors (subtypes: P2X1-7). These receptors are involved in inflammatory processes including neuroinflammation and pain sensation. The P2X4 receptor subtype has been proposed as a novel drug target for neuropathic and inflammatory pain. We have developed allosteric modulators for P2X receptor subtypes with a focus on P2X4 antagonists. Moreover we identified and characterized allosteric binding sites on the P2X4 receptor using a combination of mutagenesis studies and molecular modeling based on published X-ray structures. Recently, we succeeded in developing the first potent and selective antagonist for the UTP-activated P2Y4 receptor. The new tool compounds will allow target validation studies and may serve as lead compounds for drug development.

Design of new antagonists of P2X and P2Y receptors

254th National Meeting (2017)

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