In vitro pharmacological profile of the A2A receptor antagonist istradefylline

Abstract

Adenosine A2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson's disease (PD). Istradefylline is an adenosine A2A 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 A2A receptor antagonist. Istradefylline exhibited high affinity for A2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A1, A2B, and A3) were lower than that for A2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D1, D2, D3, D4, and D5). 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 A2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A2A 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 A2A 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.

Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists

“…It is highly expressed in the striatum and for this reason it was rapidly considered a therapeutic target in Parkinson's disease. Selective A 2A R antagonists are very safe and one of them, istradefylline, has already been approved for prescription to parkinsonian patients (Jenner, ; Jenner et al, ; Kondo et al, ; Mizuno & Kondo, ; Saki et al, ). Perspectives of A 2A R antagonists are also high to potentiate immunological innate mechanisms to combat cancer (Hatfield & Sitkovsky, ; Ohta et al, ).…”

Istradefylline is Recommended for Morning Use: A Report of 4 Cases

“…However, caffeine has many mechanisms in addition to A2AR antagonism (4), whereas ISD is a selective antagonist and its affinity for A2AR is much higher than that of caffeine (ISD, 12.4 nmol/L; caffeine, 23,400 nmol/L). Therefore, it is difficult to directly compare the effects of ISD and caffeine (5). A2ARs are expressed in striatopallidal neurons and the nucleus accumbens and are related to the mechanisms of wakefulness (4,6).…”

New Pharmacological Approaches to Treating Non-Motor Symptoms of Parkinson’s Disease

“…Istradefylline represents a novel target in the treatment of PD fatigue. Istradefylline is a competitive antagonist that selectively binds adenosine A 2A receptors more favorably than other adenosine receptors [62]. Caffeine, another adenosine antagonist, is thought to promote wakefulness by affecting A 2A receptors specifically in the nucleus accumbens shell but not the core [63].…”