The atypical antipsychotic profile of NRA0045, a novel dopamine D4 and 5-hydroxytryptamine2A receptor antagonist, in rats.
1. The atypical antipsychotic profile of (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine D4 and 5-hydroxytryptamine (5-HT)2A receptor antagonist, was examined in rats. 2. Spontaneous locomotor activity was decreased dose-dependently with i.p. administration of clozapine (ED50 3.7 mg kg-1), haloperidol (ED50 0.1 mg kg-1) and chlorpromazine (ED50 0.9 mg kg-1), whereas inhibition of this type of behaviour induced by i.p. administration of NRA0045, at doses up to 10 mg kg-1, did not exceed 50%. 3. Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg-1, i.p.) in rats (a model of antipsychotic activity) was dose-dependently antagonized by NRA0045 (ED50 0.4 mg kg-1, i.p., and 0.3 mg kg-1, p.o., respectively), clozapine (ED50 0.3 mg kg-1, i.p. and 0.8 mg kg-1, p.o., respectively), haloperidol (ED50 0.02 mg kg-1, i.p. and 0.1 mg kg-1, p.o., respectively), chlorpromazine (ED50 0.3 mg kg-1, i.p. and 3.3 mg kg-1, p.o., respectively). In contrast, the MAP (3 mg kg-1, i.v.)-induced stereotyped behaviour in rats (a model of extrapyramidal symptoms) was not affected by NRA0045 or clozapine, at the highest dose given (30 mg kg-1, i.p.). Haloperidol (ED50 0.3 mg kg-1, i.p.) and chlorpromazine (ED50 4.8 mg kg-1, i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine selectively blocked behaviour associated with activation of the mesolimbic/mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4. Extracellular single-unit recording studies demonstrated that MAP (1 mg kg-1, i.v.) decreased the firing rate in the substantia nigra (A9) and ventral tegmental area (A10) dopamine neurones in anaesthetized rats. NRA0045 completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 0.1 mg kg-1, i.v.), whereas the inhibitory effects of MAP on A9 dopamine neurones were not affected by NRA0045, in doses up to 1 mg kg-1 (i.v.). Clozapine completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 1.9 mg kg-1, i.v.) and on A9 dopamine neurones (ED50 2.5 mg kg-1, i.v.). Haloperidol completely reversed the inhibitory effects of MAP on A10 (ED50 0.03 mg kg-1, i.v.) and on A9 dopamine neurones (0.02 mg kg-1, i.v.). NRA0045, like clozapine, was more potent in reversing the effects of MAP on A10 than A9 dopamine neurones. 5. Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disruption of PPI in rats by apomorphine (0.5 mg kg-1, s.c.) was reversed significantly by NRA0045 (3 mg kg-1, i.p.), clozapine (3 mg kg-1, i.p.) and haloperidol (0.3 mg kg-1, i.p.). 6. Phencyclidine (PCP) elicits predominantly psychotic symptoms in normal humans and in schizophrenics. NRA0045 (0.03-0.3 mg kg-1, i.p.) and clozapine (0.1-1 mg kg-1, i.p.) significantly and dose-dependently shortened the PCP(1.25 mg kg-1, i.p.)-induced prolonged swimming latency in rats in a water maze task, whereas haloperidol (0.01-0.1 mg kg-1, i.p.) did not significantly alter swimming latency. 7. These findings suggest that NRA0045 may have unique antipsychotic activities without the liability of motor side effects typical of classical antipsychotics.
Okuyama
S
S
1st Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Chaki
S
S
Kawashima
N
N
Suzuki
Y
Y
Ogawa
S
S
Kumagai
T
T
Nakazato
A
A
Nagamine
M
M
Yamaguchi
K
K
Tomisawa
K
K
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008694:Methamphetamine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D050638:Receptors, Dopamine D4; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493601:Drd4 protein, rat; C106996:NRA 0045; D011759:Pyrrolidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013844:Thiazoles; D050638:Receptors, Dopamine D4; D008694:Methamphetamine; D003024:Clozapine; D001058:Apomorphine