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

Abstract

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.

The Role of Sigma Receptors in Depression

“…Recently, OPC-14523, a combined sigma 1 and 5-HT 1A receptor ligand (156), yielded interesting results in the FST (156,157). Single doses decreased immobility time and the effect of OPC-14523 was enhanced by its daily administration for 7 days.…”

“…If one accepts the hypothesis that the firing activity of 5-HT neurons represents a direct index of the efficacy of the 5-HT neurotransmission, this suggests that sigma ligands may represent antidepressants with a fast onset of action. Further studies were also conducted with the sigma 1 ligand OPC-14523, which also presents high affinity for the 5-HT 1A receptor and moderate 5-HT reuptake blocking activity (156,157). OPC-14523, similarly to other sigma ligands, induced a significant increase in the firing activity of 5-HT neurons of the DRN after 2 days of treatment.…”

Spectroscopic investigation and computational analysis of charge transfer hydrogen bonded reaction between 3-aminoquinoline with chloranilic acid in 1:1 stoichiometric ratio

“…A C C E P T E D ACCEPTED MANUSCRIPT 3 computations. Basic molecular modelling computations such as alignment, stochastic conformational sampling, dihedral driver and MM2 experiments can be effectively facilitated by using this software.…”

“…The quinoline system is a prevalent topic of research. Its presence, as key structural motifs, in a large number of bioactive drugs such as quinine, chloroquine, luotonine-A, and camptothecin has led to the design of numerous approaches towards the construction of this skeleton [1][2][3][4]. Photophysics of various quinoline derivatives has been an area of intensive research in the past few decades because of their potential applications in the synthesis of various dyes and drugs [5].…”

Anticonvulsant Activity and Toxicity Evaluation of Cu^II and Zn^II Metal Complexes Derived from Triazole-Quinoline Ligands

“…Interestingly, a considerable enhancement of activity upon complexation has been observed, 6,7) which is certainly related to the increased lipophilicity upon complexation (which increases their permeability to the blood-brain barrier) and inertness of certain metal ligand linkages towards enzymatic degradation. 8,9) Quinoline derivatives have been known to possess a variety of biological activities such as antitumor, 10) antimalarial, 11) antidepressant, 12) antiulcer 13) and cardiac stimulant. 14) Along with these, there are reports suggesting that the quinolines have exhibited a very good anticonvulsant activity in the maximum electroshock method test.…”