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-stimulating activity, we prepared a series of 1-[omega-(4-substituted phenyl-1-piperazinyl)alkyl]-3, 4-dihydro-2(1H)-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 sigma receptors by evaluating their ability to inhibit [(3)H]-1,3-di(o-tolyl)guanidine ([(3)H]DTG) binding to the rat whole brain membrane in comparison with three putative sigma receptor agonists: 1,3-di(o-tolyl)guanidine (DTG, 66), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2, 6-methano-3-benzazecin-8-ol (SKF10,047, 67), and (+)-1,2,3,4,5, 6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2, 6-methano-3-benzazecin-8-ol (pentazocine, 68). Among the series of derivatives, 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3, 4-dihydro-5-methoxy-2(1H)-quinolinone hydrochloride (34b) and its mesylate (34c), at a dose of 30 mg/kg po, reduced the sleeping time and the time for recovery from coma and they inhibited [(3)H]DTG binding for sigma receptors. The putative sigma receptor agonists reduced the sleeping time and the time for recovery from coma whereas two sigma receptor antagonists, alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride (BMY14802, 69) and cis-9-[3-(3, 5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride (rimcazole, 70), were inactive in the two tests. Preadministration of the putative sigma receptor antagonists 69 (3 mg/kg po) and 70 (30 mg/kg po) completely antagonized the actions of 34b and the sigma receptor agonists in the test for recovery from coma. These results suggested that 34b and 34c are sigma receptor agonists. Furthermore, a single administration of 1 and 10 mg/kg po 34b and 34c showed antidepressant-like activity by reducing 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 reduce the time after a single administration. 1 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.
Oshiro
Y
Y
Otsuka Pharmaceutical Company Ltd., Third Tokushima Institute of New Drug Research, 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan. yoshiro@osb.otsuka.co.jp
Sakurai
Y
Y
Sato
S
S
Kurahashi
N
N
Tanaka
T
T
Kikuchi
T
T
Tottori
K
K
Uwahodo
Y
Y
Miwa
T
T
Nishi
T
T
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D001924:Brain Concussion / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000187:drug effects / Q000627:therapeutic use; D013329:Structure-Activity Relationship
C404207:1-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-3,4-dihydro-5-methoxy-2(1H)-quinolinone; D000928:Antidepressive Agents; D010879:Piperazines; D015363:Quinolones; D017480:Receptors, sigma