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 therapeutic 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 has 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 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3-3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders.
Hodgson
Robert A
RA
Department of Neurobiology, Merck and Co. Inc., Kenilworth, NJ 07033, USA. Robert.Hodgson@Merck.com
Bedard
Paul J
PJ
Varty
Geoffrey B
GB
Kazdoba
Tatiana M
TM
Di Paolo
Therese
T
Grzelak
Michael E
ME
Pond
Annamarie J
AJ
Hadjtahar
Abdallah
A
Belanger
Nancy
N
Gregoire
Laurent
L
Dare
Aurelie
A
Neustadt
Bernard R
BR
Stamford
Andrew W
AW
Hunter
John C
JC
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D058917:Adenosine A2 Receptor Antagonists; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001479:Basal Ganglia / Q000378:metabolism*; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D002428:Cebus; D004195:Disease Models, Animal; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D011743:Pyrimidines / Q000627:therapeutic use*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D014230:Triazoles / Q000627:therapeutic use*
D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; C539997:2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine