3,4-dihydro-2(1H)-quinolinone as a novel antidepressant drug: Synthesis and pharmacology of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3,4-dihydro-5-methoxy-2(1H)-quinolinone and its derivatives

To develop a novel antidepressant drug with central nervous system-stimulat ing activity, me prepared a series of 1-[w-(4-substituted phenyl-1-piperazi nyl)alkyl]-3,4-dihydro-2(1H)-quinlinone derivatives and examined their acti vities by their effects at 30 and 100 mg/kg po on the sleeping time of mice anesthetized with halothane and on the time required for recovery from com a induced in mice by cerebral concussion. We examined their binding affinit ies for a receptors by evaluating their ability to inhibit [H-3]-1,3-di(o-t olyl)guanidine ([H-3]DTG) binding to the rat whole brain membrane in compar ison with three putative a receptor agonists: 1,3-di(o-tolyl)guanidine (DTG , 66), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethylmethano-3-benzazecin-8-ol (SK F10,047, 67), and (+)-1,2,3,4,5,6-hexahydro-6, 11-dimethyl-3(3 -methyl-2-bu tenyl)-2,6-methano-3-benzazecin-8-ol (pentazocine, 68). Among the series of derivatives, 1-3-[4-(3-chlorophenyl)-1-piperazinyl]-3p linone hydrochlorid e (34b) and its mesylate (34c), at a dose of 30 mg/kg po, reduced the sleep ing time and the time for recovery from coma and they inhibited [H-3]DTG bi nding for a receptors. The putative a receptor agonists reduced the sleepin g time and the time for recovery from coma whereas two a receptor antagonis ts, alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl) piperazinebutanol hyd rochloride (BMY14802, 69) and cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]c arbazole dihydrochloride (rimcazole, 70), were inactive in the two tests. P readministration of the putative a receptor antagonists 69 (3 mg/kg po) and 70 (30 mg/kg po) completely antagonized the actions of 34b and the a recep tor agonists in the test for recovery from coma. These results suggested th at 34b and 34c are a receptor agonists. Furthermore, a single administratio n of 1 and 10 mg/kg po 34b and 34c showed antidepressant-like activity by r educing the immobility time in the forced-swimming test with mice, while a tricyclic antidepressant, 10,11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine- 5-propanamine hydrochloride (imipramine, 1) (10 and 30 mg/kg po), did not r educe the time after a single administration. 1 reduced the time after repe ated administration of 30 mg/kg po once a day for 4 days. The structure-act ivity relationship of the series of compounds is also discussed.