In vitro and in vivo receptor binding profile of NRA0161 and NRA0562, novel atypical antipsychotics

• Published in: Japanese Journal of Pharmacology Vol. 79; no. suppl.2; p. 236
• Main Authors: Funakoshi, Takeo, Chaki, Shigeyuki, Yoshikakwa, Ryoko, Okuyama, Shigeru, Nakazato, Atsuro, Kumagai, Toshihito, Nagamine, Masashi, Tomisawa, Kazuyuki
• Format: Journal Article
• Language: English
• Published: The Japanese Pharmacological Society 1999
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1016/S0021-5198(19)34957-1

Both NRA0161 and NRA0562 showed high affinities for dopamine D_4.2 , D_3 and 5-HT_2A receptors with K_i ：values of 1.00, 3.12 and 2.52 nM (NRA0161), and 1.44, 2.68 and 1.25 nM (NRA0562), respectively. NRA0562 had high affinity for α_1 adrenoceptor (K_i ：0.40 nM) and dopamine D_2 receptor (K_i ：3.30 nM) as well. In contrast, NRA0161 had relatively high affinity for α_1 adrenoceptor (K_i ：10.44 nM), and low affinity for dopamine D_2 receptor (K_i ：94.81 nM). In vivo receptor occupancy of NRA compounds was assessed by in vivo and ex vivo receptor bindings. Both NRA0161 and NRA0562 highly occupied 5-HT_2A receptor and α_1 adrenoceptor in rat frontal cortex. In contrast, the occupancy of striatal D_2 receptor by NRA0562 was weaker, and NRA0161 did not occupy D_2 receptor. Likewise, atypical neuroleptics such as risperidone and clozapine preferentially occupied frontal cortical 5-HT_2A receptor and α_1 adrenoceptor with little occupation of striatal D_2 receptor. These results demonstrate that both NRA0161 and NRA0562 preferentially occupy 5-HT_2A receptor and α_1 adrenoceptor in the frontal cortex over striatal D_2 receptor, and this mechanism might be involved in atypical pharmacological action of NRA0161 and NRA0562.