8 research outputs found
Periventricular Preoptic Area Neurons Coactivated with Luteinizing Hormone (LH)-Releasing Hormone (LHRH) Neurons at the Time of the LH Surge Are LHRH Afferents*
JNJ-40255293, a Novel Adenosine A<sub>2A</sub>/A<sub>1</sub> Antagonist with Efficacy in Preclinical Models of Parkinson’s Disease
Adenosine A<sub>2A</sub> antagonists
are believed to have therapeutic
potential in the treatment of Parkinson’s disease (PD). We
have characterized the dual adenosine A<sub>2A</sub>/A<sub>1</sub> receptor antagonist JNJ-40255293 (2-amino-8-[2-(4-morpholinyl)Âethoxy]-4-phenyl-5<i>H</i>-indenoÂ[1,2-<i>d</i>]Âpyrimidin-5-one). JNJ-40255293
was a high-affinity (7.5 nM) antagonist at the human A<sub>2A</sub> receptor with 7-fold in vitro selectivity versus the human A<sub>1</sub> receptor. A similar A<sub>2A</sub>:A<sub>1</sub> selectivity
was seen in vivo (ED<sub>50</sub>’s of 0.21 and 2.1 mg/kg p.o.
for occupancy of rat brain A<sub>2A</sub> and A<sub>1</sub> receptors,
respectively). The plasma EC<sub>50</sub> for occupancy of rat brain
A<sub>2A</sub> 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 D<sub>2</sub> 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 A<sub>2A</sub> antagonists as potential treatments
for PD
Initial Cross-Over Test of A Positive Allosteric Modulator of Alpha-7 Nicotinic Receptors to Aid Cessation in Smokers With Or Without Schizophrenia
JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson's disease
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