Approaches for designing and discovering purinergic drugs for gastrointestinal diseases

Introduction: Purines finely modulate physiological motor, secretory, and sensory functions in the gastrointestinal tract. Their activity is mediated by the purinergic signaling machinery, including receptors and enzymes regulating their synthesis, release, and degradation. Several gastrointestinal dysfunctions are characterized by alterations affecting the purinergic system. Areas covered: The authors provide an overview on the purinergic receptor signaling machinery, the molecules and proteins involved, and a summary of medicinal chemistry efforts aimed at developing novel compounds able to modulate the activity of each player involved in this machinery. The involvement of purinergic signaling in gastrointestinal motor, secretory, and sensory functions and dysfunctions, and the potential therapeutic applications of purinergic signaling modulators, are then described. Expert opinion: A number of preclinical and clinical studies demonstrate that the pharmacological manipulation of purinergic signaling represents a viable way to counteract several gastrointestinal diseases. At present, the paucity of purinergic therapies is related to the lack of receptor-subtype-specific agonists and antagonists that are effective in vivo. In this regard, the development of novel therapeutic strategies should be focused to include tools able to control the P1 and P2 receptor expression as well as modulators of the breakdown or transport of purines