Preladenant, a selective A(2A) receptor antagonist, is active in primate models of movement disorders.
Summary of "Preladenant, a selective A(2A) receptor antagonist, is active in primate models of movement disorders."
Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D(2) receptors by antipsychotics, respectively. Adenosine A(2A) receptors are selectively localized in the basal ganglia, primarily in the striatopallidal ("indirect") pathway, where they appear to operate in concert with D(2) receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A(2A) receptor activation contributes to the overdrive of the indirect pathway. A(2A) receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A(2A) receptor antagonists have thereapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A(2A) receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A(2A) receptor antagonist, and was produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus appela monkeys with a history of chronic haloperidol treatment, preladenant (0.3 - 3.0mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use preladenant for the treatment of PD and antipsychotic-induced movement disorders.
Affiliation
Department of Neurobiology, Merck and Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Journal Details
This article was published in the following journal.
Name: Experimental neurology
ISSN: 1090-2430
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20655910
- DOI: http://dx.doi.org/10.1016/j.expneurol.2010.07.011
Medical and Biotech [MESH] Definitions
Granisetron
A serotonin receptor (5HT-3 selective) antagonist that has been used as an antiemetic for cancer chemotherapy patients.
Ketanserin
A selective serotonin receptor antagonist with weak adrenergic receptor blocking properties. The drug is effective in lowering blood pressure in essential hypertension. It also inhibits platelet aggregation. It is well tolerated and is particularly effective in older patients.
Terfenadine
A selective histamine H1-receptor antagonist devoid of central nervous system depressant activity. The drug was used for ALLERGY but withdrawn due to causing LONG QT SYNDROME.
Butoxamine
A beta-2 selective adrenergic antagonist. It is used primarily in animal and tissue experiments to characterize beta-2 receptor involvement and identify beta-2 receptors.
Raloxifene
A second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue.
PubMed Articles
The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are describ...
Straub tail reaction (STR) was observed in male ddY mice after simultaneous administration with BMY 14802 (a non-specific σ receptor antagonist) and methamphetamine (METH). The intensity and duration...
It is well known that amphetamine induces disrupted prepulse inhibition (PPI) in humans and rodents. We have previously reported that intracerebroventricular (i.c.v.) administration of p-hydroxyamphet...
MZ-4-71 is an antagonist of growth hormone-releasing hormone (GH-RH) which suppresses the secretion of GH-RH. It has been shown that MZ-4-71 has antidepressive-like effects in a modified forced swimmi...
The identification and subsequent optimisation of a selective non-peptidic NPY Y2 antagonist series is described. This led to the development of amine 2, a selective, soluble NPY Y2 receptor antagonis...
Clinical Trials
This study is to evaluate the efficacy of a range of preladenant doses compared with placebo in subjects with moderate to severe Parkinson's disease (PD) experiencing motor fluctuations an...
Oral GW766944 (Oral CCR3 Antagonist)
GW766994 is a selective, competitive antagonist of the human CC chemokine receptor-3 (CCR3). It is proposed that the inhibition of the CCR3 receptor may provide a treatment for airway in...
Anti-Interleukin-1 in Diabetes Action
A draw trial of the effect of Interleukin-1 Receptor Antagonist (anakinra, Kineret®) on the insulin production in patients with new onset Type 1 diabetes. Kineret® is already being used...
When a patient with Parkinson disease (PD) is initially treated with L dopa or dopamine agonists, the symptoms of PD improve or disappear. After several years of taking L dopa or dopamine...
The purpose of this study is to evaluate changes in left ventricular mass and cardiac function in patients with active acromegaly before and after treatment with the growth hormone recepto...
