Potential for developing purinergic drugs for gastrointestinal diseases

Treatments for inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), functional dyspepsia, or motility disorders are not adequate, and purinergic drugs offer exciting new possibilities. Gastrointestinal symptoms that could be targeted for therapy include visceral pain, inflammatory pain, dysmotility, constipation, and diarrhea. The focus of this review is on the potential for developing purinergic drugs for clinical trials to treat gastrointestinal symptoms. Purinergic receptors are divided into adenosine P1 (A(1), A(2A), A(2B), A(3)), ionotropic ATP-gated P2X ion channel (P2X(1-7)), or metabotropic P2Y(1,2,4,6,11-14) receptors. There is good experimental evidence for targeting A(2A), A(2B), A(3), P2X(7), and P2X(3) receptors or increasing endogenous adenosine levels to treat IBD, inflammatory pain, IBS/visceral pain, inflammatory diarrhea, and motility disorders. Purine genes are also potential biomarkers of disease. Advances in medicinal chemistry have an accelerated pace toward clinical trials: Methotrexate and sulfasalazine, used to treat IBD, act by stimulating CD73-dependent adenosine production. ATP protects against NSAID-induced enteropathy and has pain-relieving properties in humans. A P2X(7)R antagonist AZD9056 is in clinical trials for Crohn's disease. A(3) adenosine receptor drugs target inflammatory diseases (e.g., CF101, CF102). Dipyridamole, a nucleoside uptake inhibitor, is in trials for endotoxemia. Drugs for pain in clinical trials include P2X(3)/P2X(2/3) (AF-219) and P2X(7) (GSK1482160) antagonists and A(1) (GW493838) or A(2A) (BVT.115959) agonists. Iberogast is a phytopharmacon targeting purine mechanisms with efficacy in IBS and functional dyspepsia. Purinergic drugs have excellent safety/efficacy profile for prospective clinical trials in IBD, IBS, functional dyspepsia, and inflammatory diarrhea. Genetic polymorphisms and caffeine consumption may affect susceptibility to treatment. Further studies in animals can clarify mechanisms and test new generation drugs. Finally, there is still a huge gap in our knowledge of human pathophysiology of purinergic signaling.