8gne
Crystal structure of human adenosine A2A receptor in complex with an insurmountable inverse agonist, KW-6356.
Structural highlights
FunctionAA2AR_HUMAN Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.C562_ECOLX Electron-transport protein of unknown function. Publication Abstract from PubMedKW-6356 is a novel adenosine A(2A) (A(2A)) receptor antagonist/inverse agonist, and its efficacy as monotherapy in Parkinson's disease (PD) patients has been reported. Istradefylline is a first-generation A(2A) receptor antagonist approved for use as adjunct treatment to levodopa/decarboxylase inhibitor in adult PD patients experiencing "OFF" episodes. In this study, we investigated the in vitro pharmacological profile of KW-6356 as an A(2A) receptor antagonist/inverse agonist and the mode of antagonism and compared them with istradefylline. In addition, we determined cocrystal structures of A(2A) receptor in complex with KW-6356 and istradefylline to explore the structural basis of the antagonistic properties of KW-6356. Pharmacological studies have shown that KW-6356 is a potent and selective ligand for the A(2A) receptor (the -log of inhibition constant = 9.93 +/- 0.01 for human receptor) with a very low dissociation rate from the receptor (the dissociation kinetic rate constant = 0.016 +/- 0.006 minute(-1) for human receptor). In particular, in vitro functional studies indicated that KW-6356 exhibits insurmountable antagonism and inverse agonism, whereas istradefylline exhibits surmountable antagonism. Crystallography of KW-6356- and istradefylline-bound A(2A) receptor have indicated that interactions with His250(6.52) and Trp246(6.48) are essential for the inverse agonism, whereas the interactions at both deep inside the orthosteric pocket and the pocket lid stabilizing the extracellular loop conformation may contribute to the insurmountable antagonism of KW-6356. These profiles may reflect important differences in vivo and help predict better clinical performance. SIGNIFICANCE STATEMENT: KW-6356 is a potent and selective adenosine A(2A) receptor antagonist/inverse agonist and exhibits insurmountable antagonism, whereas istradefylline, a first-generation adenosine A(2A) receptor antagonist, exhibits surmountable antagonism. Structural studies of adenosine A(2A) receptor in complex with KW-6356 and istradefylline explain the characteristic differences in the pharmacological properties of KW-6356 and istradefylline. In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A(2A) Receptor Antagonist/Inverse Agonist.,Ohno Y, Suzuki M, Asada H, Kanda T, Saki M, Miyagi H, Yasunaga M, Suno C, Iwata S, Saito JI, Uchida S Mol Pharmacol. 2023 Jun;103(6):311-324. doi: 10.1124/molpharm.122.000633. Epub , 2023 Mar 9. PMID:36894319[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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