A selective dopamine D4 receptor antagonist, NRA0160: a preclinical neuropharmacological profile.
NRA0160, 5 - [2- ( 4- ( 3 - fluorobenzylidene) piperidin-1-yl) ethyl] - 4 -(4-fluorophenyl) thiazole-2-carboxamide, has a high affinity for human cloned dopamine D4.2, D4.4 and D4.7 receptors, with Ki values of 0.5, 0.9 and 2.7 nM, respectively. NRA0160 is over 20,000fold more potent at the dopamine D4.2 receptor compared with the human cloned dopamine D2L receptor. NRA0160 has negligible affinity for the human cloned dopamine D3 receptor (Ki=39 nM), rat serotonin (5-HT)2A receptors (Ki=180 nM) and rat alpha1 adrenoceptor (Ki=237 nM). NRA0160 and clozapine antagonized locomotor hyperactivity induced by methamphetamine (MAP) in mice. NRA0160 and clozapine antagonized MAP-induced stereotyped behavior in mice, although their effects did not exceed 50% inhibition, even at the highest dose given. NRA0160 and clozapine significantly induced catalepsy in rats, although their effects did not exceed 50% induction even at the highest dose given. NRA0160 and clozapine significantly reversed the disruption of prepulse inhibition (PPI) in rats produced by apomorphine. NRA0160 and clozapine significantly shortened the phencyclidine (PCP)-induced prolonged swimming latency in rats in a water maze task. These findings suggest that NRA0160 may have unique antipsychotic activities without the liability of motor side effects typical of classical antipsychotics.
Okuyama
S
S
1st Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Ohmiya, Saitama, Japan. S10121@ccm.taisho.co.jp
Kawashima
N
N
Chaki
S
S
Yoshikawa
R
R
Funakoshi
T
T
Ogawa
S I
SI
Suzuki
Y
Y
Ikeda
Y
Y
Kumagai
T
T
Nakazato
A
A
Nagamine
M
M
Tomisawa
K
K
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D003024:Clozapine / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004353:Drug Evaluation, Preclinical; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D050638:Receptors, Dopamine D4; D013216:Reflex, Startle / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects; D013550:Swimming; D013844:Thiazoles / Q000494:pharmacology*
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; C493600:Drd4 protein, mouse; C493601:Drd4 protein, rat; C121249:NRA 0160; D010880:Piperidines; D017448:Receptors, Dopamine D2; D013844:Thiazoles; D050638:Receptors, Dopamine D4; D008694:Methamphetamine; D003024:Clozapine