Abstract

(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, α_2A and α_2A) 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-HT_2Areceptors and alpha-1 adrenoceptor antagonistic activities, without producing the extrapyramidal side effects.