Adenosine A2A Receptor Antagonists in Drug Development

Abstract

The first A 2A adenosine receptor antagonist, istradefylline, was approved in 2013 in Japan for the treatment of Parkinson's disease (PD). This will allow long-term studies to elucidate the neuroprotective potential of A 2A antagonists in patients. New A 2A antagonists are in clinical evaluation for PD. Additional promising indications for A 2A antagonists are being explored, including Alzheimer's disease (AD) and other neurodegenerative diseases, depression, and attention deficit hyperactivity disease (ADHD). A 2A antagonists may be useful for the treatment of several rare neurodegenerative diseases, and their clinical evaluation for those diseases is warranted. Dual-and multi-target drugs combining A 2A antagonism with A 1 antagonism, MAO-B inhibition, dopamine receptor activation and/or NMDA receptor blockade may be advantageous for the treatment of PD and perhaps also for other brain diseases. X-ray structure of the human A 2A adenosine receptor in complex with several antagonists and agonists provide a basis for understanding drug-receptor interactions and support the development of new drugs.

Photoaffinity Labeling of the Human A2A Adenosine Receptor and Cross-link Position Analysis by Mass Spectrometry

“…6 Additional promising applications are currently being explored, including those for Alzheimer's disease, attention deficit hyperactivity disease, and more recently cancer immunotherapy. 7,8 Thus, ARs in particular constitute attractive targets in recent drug discovery. 9 The first X-ray structure of A 2A AR with the high-affinity antagonist ZM241385 (1) was published by Jaakola et al 10 in 2008 to reveal the inactive states of the receptor.…”

“…In our initial hA 2A AR labeling trials, we adopted the trifluoromethylphenyl diazirine (TPD) group as a photophor and the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) nucleus as a template. 25 7FB-PTP ( 6) and 8FB-PTP (7) are one of the first reported compounds having a PTP nucleus (Chart 1b). 8FB-PTP ( 7) is known as a highly potent antagonist (K i rA 2A AR = 1.2 nM), whereas 7FB-PTP (6) showed a decreased affinity (K i rA 2A AR = 12 nM).…”

“…Various A 2A AR antagonists have been developed for the treatment of Parkinson’s disease and other neurodegenerative conditions . Additional promising applications are currently being explored, including those for Alzheimer’s disease, attention deficit hyperactivity disease, and more recently cancer immunotherapy. , Thus, ARs in particular constitute attractive targets in recent drug discovery …”