A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model.
A potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonist and antagonist, ACP-103 [N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1, active:salt)], was evaluated for its ability to reduce the primary motor symptom of tremor using tacrine-induced tremulous jaw movements in rats, which is an animal model of parkinsonian tremor. Furthermore, ACP-103 was evaluated for its ability to reduce levodopa-induced dyskinesias in monkeys rendered parkinsonian with MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]. ACP-103 reduced tacrine-induced tremulous jaw movements in rats. In addition, ACP-103 administered in combination with levodopa caused a dose-related reduction in dyskinesias in monkeys. These data suggest that ACP-103 may have the potential to reduce tremor and levodopa-induced dyskinesias in Parkinson's disease.
Vanover
Kimberly E
KE
ACADIA Pharmaceuticals Inc., San Diego, CA, USA.
Betz
Adrienne J
AJ
Weber
Suzanne M
SM
Bibbiani
Francesco
F
Kielaite
Aiste
A
Weiner
David M
DM
Davis
Robert E
RE
Chase
Thomas N
TN
Salamone
John D
JD
D000818:Animals; D003627:Data Interpretation, Statistical; D015259:Dopamine Agents; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D007568:Jaw / Q000502:physiology; D007980:Levodopa; D020267:MPTP Poisoning / Q000188:drug therapy; D008252:Macaca fascicularis; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014202:Tremor / Q000188:drug therapy*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D015259:Dopamine Agents; D010880:Piperidines; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D007980:Levodopa; D014508:Urea; C510793:pimavanserin