Effects of NRA0045, NRA0160, and NRA0215 on regional Fos-like immunoreactivity in the rat brain.
Pharmacological characteristics of NRA compounds, novel atypical antipsychotics, were compared with those of clozapine and haloperidol, in regard to modification of Fos-like immunoreactivity (FLI) in rats. (R)-(+)-2-Amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045) and 2-carbamoyl-4-phenyl-5-[2-[4-(4-fluorobenzylidene) piperidin-1-yl] ethyl] thiazole (NRA0215) have a high affinity for dopamine D4 receptors, serotonin2A receptors, and the alpha1 adrenoceptor. 2-Carbamoyl-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene) piperidin-1-yl] ethyl] thiazole (NRA0160) has a selective and high affinity for dopamine D4 receptors. NRA0045 and clozapine (10 and 30 mg/kg, IP) produced significant increases in FLI in both the nucleus accumbens (N. Acc.) and the medial prefrontal cortex (mPFC) but not in the dorsolateral striatum (DLS). In contrast, NRA0160 and NRA0215 (10 and 30 mg/kg, IP) significantly increased FLI in the mPFC but not in the N. Acc. and the DLS. Haloperidol (0.1 and 1 mg/kg, IP) significantly produced FLI in the N. Acc., the DLS, and the mPFC. These data indicate that the antagonistic effects of dopamine D4 receptors may contribute, at least in part, to the actions of NRA0045, NRA0160, and NRA0215 in the mPFC.
Kawashima
N
N
First Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Ohmiya, Saitama, Japan.
Nakamura
A
A
Okuyama
S
S
Chaki
S
S
Tomisawa
K
K
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009714:Nucleus Accumbens / Q000737:chemistry / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000737:chemistry / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*
D014150:Antipsychotic Agents; C106996:NRA 0045; C121249:NRA 0160; C121248:NRA 0215; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011759:Pyrrolidines; D013844:Thiazoles; D003024:Clozapine; D006220:Haloperidol