Target Analysis - Purinoreceptors
The potential of P2 Purinoreceptors
Purinoreceptors are the cell-surface receptors for the nucleotides adenosine, ATP, ADP, UTP and UDP. This review will highlight drug discovery based on the receptors activated by ATP - a class known as the P2 purinoceptors. From the initial description of purinergic nerves by Geoffrey Burnstock in 1972, to the cloning of the first P2 purinoreceptors in the early 1990s, their existence had been a matter of hot debate. These receptors have proved readily tractable, and as we further understand their function and expression in different tissues, they continue to provide a point of therapeutic intervention in an array of disorders. Pharmaprojects' data shows that drugs targeting P2 purinoreceptors are under development for a wide range of indications including cystic fibrosis, cardiovascular disorders, depression, rheumatoid arthritis (RA) and pain (Graph 1).
P2 receptors are divided into two broad groups: P2X and P2Y. P2X receptors are multi-subunit ligand-gated ion channels activated by ATP and which non-selectively conduct cations. Seven mammalian P2X subtypes have been cloned (P2X1-7), each forming homomeric receptors with a number of known heteromeric assemblies (P2X2/3, P2X1/5 & P2X4/6). P2Y receptors on the other hand, are G-protein coupled receptors (GPCRs) of which eight subtypes are known to exist (P2Y1,2,4,6,11,12,13,14). They are linked to a variety of G-proteins and are activated in response to a number of nucleotides, including ATP, ADP UTP and UDP.
Like so many other great scientific breakthroughs, the discovery of P2 purinoreceptors was rather serendipitous. In the early 1960s, Geoffrey Burnstock and his two students at the University of Melbourne, Australia, stumbled across autonomic neurotransmission which they believed was mediated by a novel transmitter. The traditional view of the autonomic nervous system at the time was that it comprised adrenergic and cholinergic nerves. Whilst examining intestinal smooth muscle, Burnstock observed that a rapid hyperpolarization of the muscle persisted in the presence of both cholinergic and adrenergic antagonists, indicating a third type of nerve, simply named non-adrenergic, noncholinergic (NANC). This finding was strengthened by the detection of excitatory NANC transmission in blood vessels and the bladder, and so the hunt for this mysterious transmitter ensued.
It was in 1972 with Burnstock's landmark paper 'Purinergic Nerves' that the world was first introduced to ATP as a neurotransmitter and it was not until some 20 years later that the concept proposed by Burnstock was widely accepted. The idea that ATP could function as an extracellular transmitter was controversial due to the fact it was is ubiquitous in the body. Some of Burnstock's peers at the time were so incensed that he could suggest such a hypothesis that they vowed to devote their lives to destroying it. The majority of the scientific community continued to reject Burnstock's proposal until the first of many P2 purinoreceptors were cloned and characterized in the early 1990s.
