Vol. 282, Issue 1, 56-63, 1997

In Vitro and In Vivo Characterization of the Dopamine D₄ Receptor, Serotonin 5-HT_2A Receptor and Alpha-1 Adrenoceptor Antagonist (R)-(+)-2-Amino-4-(4-Fluorophenyl)- 5-[1-[4-(4-Fluorophenyl)-4-Oxobutyl]Pyrrolidin-3-yl]Thiazole (NRA0045)

Shigeru Okuyama , Shigeyuki Chaki, Ryoko Yoshikawa, Yoshiko Suzuki, Shin-Ichi Ogawa, Yasuko Imagawa , Naoya Kawashima, Yoko Ikeda, Toshihito Kumagai, Atsuro Nakazato, Masashi Nagamine and Kazuyuki Tomisawa

1st Laboratory (S.O., S.C., R.Y., Y.S., S.O., Y.I., N.K., T.K., N.A., K.T.) and Molecular Biology Laboratory (Y.I.), Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Ohmiya, Saitama 330, Japan and Research Center (M.N.), Nihon Nouyaku Co., Ltd., Kawachi-Nagano, Osaka 586, Japan

(R)-(+)-2-Amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]pyrrolidin-3-yl]thiazole (NRA0045), a novel thiazole derivative, has high affinities for the human cloned dopamine D_4.2, D_4.4 and D_4.7 receptors, with K_i values of 2.54, 0.55 and 0.54 nM, respectively. NRA0045 is approximately 91-fold more potent at the dopamine D_4.2 receptor, compared with human cloned dopamine D_2L receptor. NRA0045 also has high affinities for the serotonin (5-HT)_2A receptor (K_i = 1.92 nM) and alpha-1 adrenoceptor (K_i = 1.40 nM) but weak affinities (IC₅₀ values are approximately 1 µM) for six other neurotransmitter receptors (adenosine₁, 5-HT_1A, 5-HT_1C, dopamine transporter, _2A and _2A) and negligible affinities (IC₅₀ values are over 10⁵ M) for 42 other receptors, including neurotransmitters and hormones, ion channels and second messenger systems. Locomotor hyperactivity induced by methamphetamine (1 mg/kg i.p.) in mice was dose-dependently antagonized by NRA0045 (ED₅₀ = 0.5 mg/kg i.p. and 1.9 mg/kg p.o., respectively). Methamphetamine (10 mg/kg i.p.)-induced stereotyped behavior in mice was dose-dependently antagonized by NRA0045, whereas NRA0045 did not exceed 50% inhibition even at the highest dose given (30 mg/kg i.p.). Catalepsy was dose-dependently and significantly induced by NRA0045 in rats, whereas NRA0045 did not exceed 50% induction even at the highest dose given (30 mg/kg i.p.). Thus NRA0045 blocks behaviors associated with activation of the mesolimbic/mesocortical dopaminergic neurons more selectively than behaviors associated with nigrostriatal dopaminergic neurons. In rats, tryptamine-induced clonic seizure, a 5-HT₂ receptor-mediated behavior, was also dose-dependently inhibited by NRA0045 (ED₅₀ = 1.7 mg/kg i.p.). Norepinephrine-induced lethality is regarded as being induced through the alpha-1 adrenoceptor. NRA0045 dose-dependently antagonized norepinephrine-induced lethality in rats (ED₅₀ = 0.2 mg/kg i.p.). Thus NRA0045 may have a unique antipsychotic activity with regard to dopamine D₄ and 5-HT_2A receptors and alpha-1 adrenoceptor antagonistic activities, without producing the extrapyramidal side effects.