Challenges in developing P2 purinoceptor-based therapeutics

Advances in the molecular cloning, expression and functional characterization of the P2 purinoceptor superfamily have provided a wealth of data to support a diverse functional role for ATP and related nucleotides in the regulation of tissue function. As with other receptor superfamilies, it is likely that distinct subtypes of each receptor will subserve discrete functions depending on tissue distribution and disease pathophysiology. At the present time, ATP is being evaluated as an anticancer agent and as an anaesthesia adjunct whereas UTP is studied as a novel treatment for cystic fibrosis. ARL67085 is a potent and selective P2T receptor antagonist that has potential as a novel antithrombotic agent. The key to exploiting the P2 purinoceptor area to enhance understanding of disease aetiology and concurrent therapeutic potential will be to focus efforts on the identification of novel pharmacophores that have potent and selective interactions with the various receptor subtypes as potential new leads. To this end, the use of high-throughput screening in conjunction with combinatorial chemical, conventional chemical and natural product library compound sources will be critical.