JNJ-40255293, a Novel Adenosine A2A/A1 Antagonist with Efficacy in Preclinical Models of Parkinson鈥檚 Disease

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• 作者：John R. Atack ; Brian C. Shook ; Stefanie Rassnick ; Paul F. Jackson ; Kenneth Rhodes ; Wilhelmus H. Drinkenburg ; Abdallah Ahnaou ; Paula te Riele ; Xavier Langlois ; Brian Hrupka ; Patrick De Haes ; Herman Hendrickx ; Nancy Aerts ; Koen Hens ; Annemie Wellens ; Jef Vermeire ; Anton A. H. P. Megens
• 刊名：ACS Chemical Neuroscience
• 出版年：2014
• 出版时间：October 15, 2014
• 年：2014
• 卷：5
• 期：10
• 页码：1005-1019
• 全文大小：631K
• ISSN：1948-7193

文摘

Adenosine A_2A antagonists are believed to have therapeutic potential in the treatment of Parkinson鈥檚 disease (PD). We have characterized the dual adenosine A_2A/A₁ receptor antagonist JNJ-40255293 (2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one). JNJ-40255293 was a high-affinity (7.5 nM) antagonist at the human A_2A receptor with 7-fold in vitro selectivity versus the human A₁ receptor. A similar A_2A:A₁ selectivity was seen in vivo (ED₅₀鈥檚 of 0.21 and 2.1 mg/kg p.o. for occupancy of rat brain A_2A and A₁ receptors, respectively). The plasma EC₅₀ for occupancy of rat brain A_2A receptors was 13 ng/mL. In sleep鈥搘ake encephalographic (EEG) studies, JNJ-40255293 dose-dependently enhanced a consolidated waking associated with a subsequent delayed compensatory sleep (minimum effective dose: 0.63 mg/kg p.o.). As measured by microdialysis, JNJ-40255293 did not affect dopamine and noradrenaline release in the prefrontal cortex and the striatum. However, it was able to reverse effects (catalepsy, hypolocomotion, and conditioned avoidance impairment in rats; hypolocomotion in mice) produced by the dopamine D₂ antagonist haloperidol. The compound also potentiated the agitation induced by the dopamine agonist apomorphine. JNJ-40255293 also reversed hypolocomotion produced by the dopamine-depleting agent reserpine and potentiated the effects of l-dihydroxyphenylalanine (L-DOPA) in rats with unilateral 6-hydroxydopamine-induced lesions of the nigro-striatal pathway, an animal model of Parkinson鈥檚 disease. Extrapolating from the rat receptor occupancy dose鈥搑esponse curve, the occupancy required to produce these various effects in rats was generally in the range of 60鈥?0%. The findings support the continued research and development of A_2A antagonists as potential treatments for PD.

Keywords:

Parkinson鈥檚 disease; adenosine; A_2A antagonists; neuropharmacology; dopamine; neurodegeneration