In vitro pharmacological profile of the A2A receptor antagonist istradefylline

Adenosine A(2A) receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson's disease (PD). Istradefylline is an adenosine A(2A) receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro pharmacological profile of istradefylline as an A(2A) receptor antagonist. Istradefylline exhibited high affinity for A(2A) receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A(1), A(2B), and A(3)) were lower than that for A(2A) receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D-1, D-2, D-3, D-4, and D-5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol-O-methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A(2A) receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A(2A) agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration-response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A(2A) receptor antagonist. The in vitro pharmacological profile of istradefylline helps to explain the in vivo profile of istradefylline and may be useful for clinical pharmacokinetic-pharmacodynamic considerations of efficacy and safety.