title: In vivo receptor occupancy of NRA0045, a putative atypical antipsychotic, in rats.
abstract: We have previously reported that (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]+ ++pyrrolidin-3-yl]thiazole (NRA0045) is a novel antipsychotic agent with affinities for dopamine D4, 5-hydroxytryptamine 2A (5-HT2A) and alpha1 receptors. In the present study, in vivo receptor occupancy of 5-HT2A, alpha1, dopamine D2 and D3 receptors by NRA0045 was assessed, based on in vivo and ex vivo receptor binding, and findings were compared to reference antipsychotic drugs (haloperidol, risperidone, clozapine). Intraperitoneal administration of haloperidol highly occupied the dopamine D2 receptor in the striatum and nucleus accumbens, and alpha1 adrenoceptors in the frontal cortex. Occupation of the 5-HT2A receptor in the frontal cortex and the dopamine D3 receptor in the nucleus accumbens and islands of Cajella was moderate. By contrast, atypical antipsychotics such as risperidone and clozapine dose-dependently occupied the 5-HT2A receptor in the frontal cortex, with moderate to negligible occupancy of the D2 receptor in the striatum and the nucleus accumbens. Clozapine and risperidone also occupied the alpha1 adrenoceptor in the frontal cortex, and clozapine did not occupy the dopamine D3 receptor. As seen with other atypical antipsychotics, intraperitoneal administration of NRA0045 dose-dependently occupied the 5-HT2A receptor and the alpha1 adrenoceptor in the frontal cortex, while it was without effect on dopamine D2 and D3 receptors in the striatum, nucleus accumbens and islands of Cajella. Thus, the strong occupancy of 5-HT2A and alpha1 receptors is involved in the pharmacological action of NRA0045.
authors.affiliation: 1st Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Ohmiya, Saitama, Japan. s13555@ccm.taisho.co.jp
authors.forename: S
authors.initials: S
authors.lastname: Chaki
authors.forename: T
authors.initials: T
authors.lastname: Funakoshi
authors.forename: R
authors.initials: R
authors.lastname: Yoshikawa
authors.forename: S
authors.initials: S
authors.lastname: Okuyama
authors.forename: T
authors.initials: T
authors.lastname: Kumagai
authors.forename: A
authors.initials: A
authors.lastname: Nakazato
authors.forename: M
authors.initials: M
authors.lastname: Nagamine
authors.forename: K
authors.initials: K
authors.lastname: Tomisawa
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D018967:Risperidone / Q000494:pharmacology; D012559:Schizophrenia / Q000188:drug therapy; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; C106996:NRA 0045; D011759:Pyrrolidines; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D013844:Thiazoles; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone