Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design

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 , A_2A , A_2B, 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 P2Y₁ R antagonists and anti-inflammatory P2Y₁₄ R antagonists and A₃ AR agonists. A₃ AR agonists are a potential, nonaddictive treatment for chronic neuropathic pain.