Comparative study of 2-(4-ethyl-1-piperazinyl)-4-(fluorophenyl)-5,6,7,8,9, 10-hexahydrocycloocta[b]pyridine (AD-5423) and haloperidol for their pharmacological activities related to antipsychotic efficacy and/or adverse side-effects.
Pharmacological effects of the novel antipsychotic, 2-(4-ethyl-1-piperazinyl)-4-(fluorophenyl)-5,6,7,8,9,10-hexahydrocycl oocta [b]pyridine (AD-5423), were compared with those of haloperidol in rats. AD-5423 suppressed hyperactivity induced by microinjecting dopamine into the nucleus accumbens (0.3-3 mg/kg p.o.), and also antagonized both apomorphine- and methamphetamine-induced decreases in firing rate of neurons in the medial prefrontal cortex (1 mg/kg i.v.), indicating antidopaminergic effects of the compound in the possible brain areas involved in pathophysiology of schizophrenia. During repeated treatment with AD-5423 (0.5 and 1 mg/kg/day p.o.), the antiavoidance effect (predictive of antipsychotic efficacy) persisted at least for 14 days, whereas tolerance developed as rapidly as within 10 days to the antagonistic effect on apomorphine-induced gnawing (predictive of acute extrapyramidal side-effects). In these tests, AD-5423 was quite similar to haloperidol in potencies and time-course patterns of the effects. However, different results were obtained between the effects of AD-5423 and haloperidol in possible animal models of tardive dyskinesia and malignant syndrome. In rats treated for 21 days with haloperidol (3 mg/kg, once a day p.o.) and (+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine [(+)SCH23390] (0.05 mg/kg, twice a day s.c.), but not with AD-5423 (10 mg/kg, once a day p.o.), 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF38393) induced a greater number of vacuous oral movements than in nontreated rats. Unlike haloperidol (3 mg/kg p.o.), AD-5423 (10 mg/kg p.o.) did not cause hyperthermia in combined treatment with veratrine (into the preoptic anterior hypothalamus).(ABSTRACT TRUNCATED AT 250 WORDS)
Noda
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Y
Department of Pharmacology, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Kurumiya
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S
Miura
Y
Y
Oka
M
M
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D004357:Drug Synergism; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects; D014702:Veratrine / Q000494:pharmacology
D014150:Antipsychotic Agents; D010879:Piperazines; D010880:Piperidines; D011954:Receptors, Dopamine; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C079310:blonanserin; D014702:Veratrine; D006220:Haloperidol; D001058:Apomorphine