The purinergic signaling system includes membrane-bound receptors for extracellular purines and pyrimidines, and enzymes/transporters that regulate receptor activation by endogenous agonists. Receptors include: adenosine (A1, A2A, A2B, and A3) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) receptors (all GPCRs), as well as P2X receptors (ion channels). Receptor activation, especially accompanying physiological stress or damage, creates a temporal sequence of signaling to counteract this stress and either mobilize (P2Rs) or suppress (ARs) immune responses. Thus, modulation of this large signaling family has broad potential for treating chronic diseases. Experimentally determined structures represent each of the three receptor families. We focus on selective purinergic agonists (A1, A3), antagonists (A3, P2Y14), and allosteric modulators (P2Y1, A3). Examples of applying structure-based design, including the rational modification of known ligands, are presented for antithrombotic P2Y1R antagonists and anti-inflammatory P2Y14R antagonists and A3AR agonists. A3AR agonists are a potential, nonaddictive treatment for chronic neuropathic pain.
Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design
Salmaso V.;
2020
Abstract
The purinergic signaling system includes membrane-bound receptors for extracellular purines and pyrimidines, and enzymes/transporters that regulate receptor activation by endogenous agonists. Receptors include: adenosine (A1, A2A, A2B, and A3) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) receptors (all GPCRs), as well as P2X receptors (ion channels). Receptor activation, especially accompanying physiological stress or damage, creates a temporal sequence of signaling to counteract this stress and either mobilize (P2Rs) or suppress (ARs) immune responses. Thus, modulation of this large signaling family has broad potential for treating chronic diseases. Experimentally determined structures represent each of the three receptor families. We focus on selective purinergic agonists (A1, A3), antagonists (A3, P2Y14), and allosteric modulators (P2Y1, A3). Examples of applying structure-based design, including the rational modification of known ligands, are presented for antithrombotic P2Y1R antagonists and anti-inflammatory P2Y14R antagonists and A3AR agonists. A3AR agonists are a potential, nonaddictive treatment for chronic neuropathic pain.Pubblicazioni consigliate
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