3,4-Dihydro-2(1<i>H</i>)-quinolinone as a Novel Antidepressant Drug:  Synthesis and Pharmacology of 1-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-3,4- dihydro-5-methoxy-2(1<i>H</i>)-quinolinone and Its Derivatives

To develop a novel antidepressant drug with central nervous system-stimulating activity, we prepared a series of 1-[ω-(4-substituted phenyl-1-piperazinyl)alkyl]-3,4-dihydro-2(1<i>H</i>)-quinolinone derivatives and examined their activities 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 coma induced in mice by cerebral concussion. We examined their binding affinities for σ receptors by evaluating their ability to inhibit [<sup>3</sup>H]-1,3-di(<i>o</i>-tolyl)guanidine ([<sup>3</sup>H]DTG) binding to the rat whole brain membrane in comparison with three putative σ receptor agonists:  1,3-di(<i>o</i>-tolyl)guanidine (DTG, <b>66</b>), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazecin-8-ol (SKF10,047, <b>67</b>), and (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazecin-8-ol (pentazocine,<b> 68</b>). Among the series of derivatives, 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3,4-dihydro-5-methoxy-2(1<i>H</i>)-quinolinone hydrochloride <b>(34b)</b> and its mesylate <b>(34c)</b>, at a dose of 30 mg/kg po, reduced the sleeping time and the time for recovery from coma and they inhibited [<sup>3</sup>H]DTG binding for σ receptors. The putative σ receptor agonists reduced the sleeping time and the time for recovery from coma whereas two σ receptor antagonists, α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride (BMY14802, <b>69) </b>and <i>cis</i>-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride (rimcazole, <b>70), </b>were inactive in the two tests. Preadministration of the putative σ receptor antagonists <b>69</b> (3 mg/kg po) and <b>70</b> (30 mg/kg po) completely antagonized the actions of <b>34b</b> and the σ receptor agonists in the test for recovery from coma. These results suggested that <b>34b</b> and <b>34c</b> are σ receptor agonists. Furthermore, a single administration of 1 and 10 mg/kg po <b>34b</b> and <b>34c</b> showed antidepressant-like activity by reducing the immobility time in the forced-swimming test with mice, while a tricyclic antidepressant, 10,11-dihydro-<i>N,N</i>-dimethyl-5<i>H</i>-dibenz[<i>b,f</i>]azepine-5-propanamine hydrochloride (imipramine,<b> 1)</b> (10 and 30 mg/kg po), did not reduce the time after a single administration. <b>1</b> reduced the time after repeated administration of 30 mg/kg po once a day for 4 days. The structure−activity relationship of the series of compounds is also discussed.