In vitro and in vivo pharmacological profile of 5-[2-[4-(6-fluoro-1H-indole-3-yl)piperidin-1-yl]ethyl]-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide (NRA0562), a novel and putative atypical antipsychotic.
In vitro and in vivo pharmacological properties of 5-[2-[4-(6-fluoro-1H-indole-3-yl)piperidin-1-yl]ethyl]-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide (NRA0562), a novel atypical antipsychotic, were investigated. NRA0562 showed high affinities for human cloned dopamine D(1), D(2), D(3) and D(4) receptors with Ki values of 7.09, 2.49, 3.48 and 1.79 nM. In addition, NRA0562 had high affinities for the 5-HT(2A) receptor and the alpha(1) adrenoceptor with Ki values of 1.5 and 0.56 nM, and moderate affinity for the histamine H(1) receptor. Using in vivo and ex vivo receptor binding studies in rats, we showed NRA0562 occupied frontal cortical 5-HT(2A) receptors and alpha(1) adrenoceptor potently, while occupancy of striatal dopamine D(2) receptor was moderate as were other atypical antipsychotics. NRA0562 dose-dependently inhibited methamphetamine (MAP)-induced locomotor hyperactivity in rats. At higher dosage, NRA0562 dose-dependently antagonized MAP-induced stereotyped behavior and induced catalepsy dose-dependently and significantly in rats. But, the ED(50) value in inhibiting MAP-induced locomotion hyperactivity was 10 times lower than that in inhibiting MAP-induced stereotyped behavior, and 30 times lower than that in inducing catalepsy. In addition, the potency of NRA0562 in antagonizing MAP-induced hyperactivity in rats was higher than that of other antipsychotics, clozapine, risperidone and olanzapine. NRA0562 had favorable properties in view of prediction of extrapyramidal side effects. As this antipsychotic has a unique profile with affinity and occupancy for receptors, we propose that NRA0652 may have unique atypical antipsychotic activities, and a moderate liability of extrapyramidal motor side effects seen in the treatment with classical antipsychotics.
Funakoshi
Takeo
T
CNS Diseases Research, Medicinal Pharmacology Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Saitama, Saitama 330-8530, Japan. t.funakoshi@po.rd.taisho.co.jp
Chaki
Shigeyuki
S
Kawashima
Naoya
N
Suzuki
Yoshiko
Y
Yoshikawa
Ryoko
R
Kumagai
Toshihito
T
Nakazato
Atsuro
A
Kameo
Kazuya
K
Goto
Makoto
M
Okuyama
Shigeru
S
D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003024:Clozapine / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D011954:Receptors, Dopamine / Q000378:metabolism; D011955:Receptors, Drug / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D018967:Risperidone / Q000493:pharmacokinetics / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
C433508:5-(2-(4-(6-fluoro-1H-indole-3-yl)piperidine-1-yl)ethyl)-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1; D011954:Receptors, Dopamine; D011955:Receptors, Drug; D011985:Receptors, Serotonin; D013844:Thiazoles; D008694:Methamphetamine; D003024:Clozapine; D018967:Risperidone