New purine derivatives as P2X3 receptor antagonists

P2X3 receptors (P2X3Rs) play an important role in neuropathic and chronic pain pathways; hence, novel P2X3R antagonists are potential agents for the treatment of chronic pain conditions and migraine. Based on molecular modeling studies, a new series of 2,6-diaminopurine derivatives bearing a substituted benzyl chain in 9-position and lipophilic substituents in N6-position were synthesized. The new derivatives were evaluated on rat P2X3Rs by using patch clamp recording from HEK-transfected cells, and some selected ones were also tested at human and at native P2X3Rs expressed by trigeminal ganglion (TG) sensory neurons in culture. Furthermore, since P2X3Rs expressing sensory neurons such as TG neurons are known to express also 5-HT and GABA receptors, this property was used to evaluate the selectivity of the new molecules. Biological results showed that the new compounds behave as antagonists of P2X3Rs; one of themappears to be potent on both recombinant and native P2X3Rs and, besides that, to substantially inhibit the 5-HT3 receptor subtype. Since studies with 5-HT3 receptor antagonists and knockout mice revealed that these receptors are positively involved in nociception and pain transduction, the novel antagonist might produce an analgesic effect due to the block of not only P2X3 but also 5-HT3 receptors of sensory neurons.