In Vitro and In Vivo Characterization of the Dopamine D4 Receptor, Serotonin 5-HT2AReceptor and Alpha-1 Adrenoceptor Antagonist (R)-(+)-2-Amino-4-(4-Fluorophenyl)- 5-[1-[4-(4-Fluorophenyl)-4-Oxobutyl]Pyrrolidin-3-yl]Thiazole (NRA0045)

• Published in: The Journal of pharmacology and experimental therapeutics 1997-07, Vol.282 (1), p.56-63
• Main Authors: Okuyama, Shigeru, Chaki, Shigeyuki, Yoshikawa, Ryoko, Suzuki, Yoshiko, Ogawa, Shin-Ichi, Imagawa, Yasuko, Kawashima, Naoya, Ikeda, Yoko, Kumagai, Toshihito, Nakazato, Atsuro, Nagamine, Masashi, Tomisawa, Kazuyuki
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1016/S0022-3565(24)36800-4

(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 D4.2, D4.4 and D4.7 receptors, with Ki values of 2.54, 0.55 and 0.54 nM, respectively. NRA0045 is approximately 91-fold more potent at the dopamine D4.2 receptor, compared with human cloned dopamine D2L receptor. NRA0045 also has high affinities for the serotonin (5-HT)2A receptor (Ki = 1.92 nM) and alpha-1 adrenoceptor (Ki = 1.40 nM) but weak affinities (IC50 values are approximately 1 μM) for six other neurotransmitter receptors (adenosine1, 5-HT1A, 5-HT1C, dopamine transporter, α2A and α2A) and negligible affinities (IC50 values are over 10−5 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-HT2Areceptors and alpha-1 adrenoceptor antagonistic activities, without producing the extrapyramidal side effects.