AMPD2 Inhibitors

Chemical inhibitors of AMPD2 can exert their inhibitory effects through various biochemical pathways related to purine metabolism and energy homeostasis. MRS2578, as a P2Y6 receptor antagonist, can disrupt purinergic signaling, leading to a decrease in purine nucleotide availability and hence a reduction in AMPD2 substrate levels. Similarly, ARL 67156's inhibition of ecto-ATPase activity can elevate extracellular ATP, potentially causing feedback inhibition of intracellular ATP decomposition and thereby reducing AMPD2 activity due to altered ATP/AMP ratios. Suramin, with its ability to block multiple purinergic receptors, can also diminish the utilization of purines, thereby decreasing AMPD2 activity as a result of reduced substrate accessibility. Sodium azide targets the mitochondrial electron transport chain and lessens ATP production, which can result in increased AMP levels that can feedback inhibit AMPD2 via product inhibition.

Dipyridamole impedes nucleoside transport, which can lead to heightened extracellular adenosine levels and subsequently reduced intracellular nucleotide pools, thus limiting AMPD2 substrate availability. EHNA, by inhibiting adenosine deaminase, can increase adenosine levels and upset the equilibrium of purine metabolism, leading to AMPD2 inhibition. Both allopurinol and its metabolite oxypurinol inhibit xanthine oxidase, potentially reducing purine degradation and subsequently the availability of AMP for AMPD2, thereby inhibiting its function. Ribavirin, being a nucleoside analogue, can deplete intracellular nucleotide pools, which in turn can inhibit AMPD2. Clopidogrel, an ADP receptor inhibitor, can affect purinergic pathways, influencing the balance of nucleotides in the cell and thus inhibiting AMPD2. Lastly, levamisole's inhibition of phosphodiesterases affects cAMP levels and, consequently, the AMP/ATP ratio, which can lead to a decrease in AMPD2 activity.