IN-VITRO AND IN-VIVO CHARACTERIZATION OF THE DOPAMINE D-4 RECEPTOR, SEROTONIN 5-HT2A RECEPTOR AND ALPHA-1-ADRENOCEPTOR ANTAGONIST -FLUOROPHENYL)-4-OXOBUTYL]PYRROLIDIN-3-YL]THIAZOLE (NRA0045)())

-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) bu t weak affinities (IC50 values are approximately 1 mu M) for six other neurotransmitter receptors (adenosine(1), 5-HT1A, 5-HT1C, dopamine tr ansporter, alpha(2A) and alpha(2A)) and negligible affinities (IC50 va lues are over 10(-5) M) for 42 other receptors, including neurotransmi tters and hormones, ion channels and second messenger systems. Locomot or 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 s tereotyped behavior in mice was dose-dependently antagonized by NRA004 5, whereas NRA0045 did not exceed 50% inhibition even at the highest d ose given (30 mg/kg i.p.). Catalepsy was dose-dependently and signific antly induced by NRA0045 in rats, whereas NRA0045 did not exceed 50% i nduction even at the highest dose given (30 mg/kg i.p.). Thus NRA0045 blocks behaviors associated with activation of the mesolimbic/mesocort ical dopaminergic neurons more selectively than behaviors associated w ith nigrostriatal dopaminergic neurons. In rats, tryptamine-induced cl onic seizure, a 5-HT2 receptor-mediated behavior, was also dose-depend ently inhibited by NRA0045 (ED50 = 1.7 mg/kg i.p.). Norepinephrine-ind uced lethality is regarded as being induced through the alpha-1 adreno ceptor. NRA0045 dose-dependently antagonized norepinephrine-induced le thality in rats (ED50 = 0.2 mg/kg i.p.). Thus NRA0045 may have a uniqu e antipsychotic activity with regard to dopamine D-4 and 5-HT2A recept ors and alpha-1 adrenoceptor antagonistic activities, without producin g the extrapyramidal side effects.