title: JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson's disease.
abstract: Adenosine A2A antagonists are believed to have therapeutic potential in the treatment of Parkinson's disease (PD). We have characterized the dual adenosine A2A/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 A2A receptor with 7-fold in vitro selectivity versus the human A1 receptor. A similar A2A:A1 selectivity was seen in vivo (ED50's of 0.21 and 2.1 mg/kg p.o. for occupancy of rat brain A2A and A1 receptors, respectively). The plasma EC50 for occupancy of rat brain A2A receptors was 13 ng/mL. In sleep-wake 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's disease. Extrapolating from the rat receptor occupancy dose-response curve, the occupancy required to produce these various effects in rats was generally in the range of 60-90%. The findings support the continued research and development of A2A antagonists as potential treatments for PD.
authors.affiliation: Janssen Research and Development , Welsh and McKean Roads, Spring House, Pennsylvania 19477, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Brian C
authors.initials: BC
authors.lastname: Shook
authors.forename: Stefanie
authors.initials: S
authors.lastname: Rassnick
authors.forename: Paul F
authors.initials: PF
authors.lastname: Jackson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rhodes
authors.forename: Wilhelmus H
authors.initials: WH
authors.lastname: Drinkenburg
authors.forename: Abdallah
authors.initials: A
authors.lastname: Ahnaou
authors.forename: Paula
authors.initials: P
authors.lastname: Te Riele
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Brian
authors.initials: B
authors.lastname: Hrupka
authors.forename: Patrick
authors.initials: P
authors.lastname: De Haes
authors.forename: Herman
authors.initials: H
authors.lastname: Hendrickx
authors.forename: Nancy
authors.initials: N
authors.lastname: Aerts
authors.forename: Koen
authors.initials: K
authors.lastname: Hens
authors.forename: Annemie
authors.initials: A
authors.lastname: Wellens
authors.forename: Jef
authors.initials: J
authors.lastname: Vermeire
authors.forename: Anton A H P
authors.initials: AA
authors.lastname: Megens
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D016466:CHO Cells; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007192:Indenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C000599367:2-amino-8-(2-(4-morpholinyl)ethoxy)-4-phenyl-5H-indeno(1,2-d)pyrimidin-5-one; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D007192:Indenes; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D011994:Recombinant Proteins; D004298:Dopamine; D009638:Norepinephrine
keywords: A2A antagonists; Parkinson’s disease; adenosine; dopamine; neurodegeneration; neuropharmacology