Jacobson – 2024

Synthesis of Pharmacological Activity of Selective PY2 Receptor Antagonists

We study the structure and pharmacology of receptors and discover drugs that act as agonists or antagonists of G protein-coupled receptors (GPCRs). Our current focus is on receptors for purines, encompassing both adenosine receptors and P2 receptors, which are activated by ATP, UTP and other extracellular nucleotides. Purinergic signaling pathways operate in nearly every tissue in the body, and there is much potential for drug discovery by modulating these pathways. We have taken an interdisciplinary approach to studying the chemical and biological aspects of these receptors using convergent modeling, mutagenesis and structure-based approaches. Detailed information about the three-dimensional structure of this receptor family aids in the design and chemical synthesis of novel ligands. We collaborate with structural biologists on determining experimental structures of various purine (adenosine and P2Y) receptors. Two agonists of the A3 adenosine receptor (both discovered in our lab) have progressed to advanced clinical trials for the treatment of autoimmune inflammatory diseases, liver diseases and cancer. We are currently designing P2Y receptor antagonists and adenosine receptor agonists for use in treating chronic neuropathic pain, an unmet medical need, and inflammation.