Pharmacology of a new sleep inducer, 1H-1, 2, 4-triazolyl benzophenone derivative, 450191-S (II)

YAMAMOTO Ken-ichi, MATSUSHITA Akira, SAWADA Tohru, NAITO Yukio, YOSHIMURA Kohji, TAKESUE Hideo, UTSUMI Shizuo, KAWASAKI Kazuo, HIRONO Satoru, KOSHIDA Hikaru, TAZAKI Takenobu

doi:10.1254/fpj.84.25

The sleep-inducing activity and effect on the motor system of the 1H-1, 2, 4-triazolyl benzophenone derivative 450191-S were examined behaviorally, electroencephalographically and electro-physiologically with various species of animals and were compared with those of diazepam, nitrazepam, estazolam and triazolam. In the rhesus monkey, rabbit and rat with chronically indwelling brain electrodes, 0.6 to 3 mg/kg, p.o. of 450191-S caused a shorter latency of sleep onset, an increase of and a stable continuity of slow wave deep sleep (SWDS) with higher amplitude, and the appearance of clear spindle bursts in the slow wave light sleeping (SWLS) state with little muscle relaxation. Animals treated with nitrazepam and/or estazolam showed a smaller increase in SWDS and its unstable continuity with remarkable disturbance of gait. The doses needed to induce sleep in the rhesus monkey were 0.6 to 1 mg/kg p.o. for 450191-S, 3 mg/kg for nitrazepam, 1 mg/kg for estazolam and 0.3 mg/kg for triazolam. The cat treated with 450191-S showed the phenomena caused by benzodiazepines (BDZ), i.e., behavioral excitation and decrease of frequencies in the hippocampal theta waves. The suppressive effects of 450191-S on the EEG arousal reaction and/or blood pressure elevation induced by hypothalamic stimulation in the rabbit suggested that the inhibitory effects acted on the posterior hypothalamus to the limbic system. The inhibitory effect of 450191-S on the amygdaloid kindling in the rat was as potent as those of diazepam and nitrazepam. Successive daily oral administration of both 3 mg/kg of 450191-S and/or 3 to 6 mg/kg of nitrazepam for 15 days in the rabbit caused slight decrease of SWDS and increase of fast wave (REM) sleep (FWS). During the withdrawal period of both compounds, a slight but insignificant increase in the waking state was noticed for I to 2 days, but not a rebound increase of FWS. Intravenously administered 450191-S showed the same action as BDZ on the spinal reflex and the dorsal root potential of the rat; it particularly acted on the crossed extensor reflex in the same manner as the commercial BDZ sleep inducers. Various examinations showed that the muscle relaxation effect of 450191-S was the weakest among the control sleep inducers, and the ratio between the increase in SWDS and the disturbance of gait in the rhesus monkey and/or the ratio between the suppressive effect on the hypothalamically induced blood pressure elevation and the inhibition of respiratory movement in the cat indicated that the compound might be a safe sleep inducer characterized by a wide dissociation between its major effect of sleep induction and its side effect of muscle relaxation. The pharmacological effects of active metabolites of 450191-S in blood such as M-1, M-2, M-A, M-3 and M-4 were compared with those of 450191-S, and the superiority of the mother compound was clarified.

Pharmacology of a new sleep inducer, 1H-1, 2, 4-triazolyl benzophenone derivative, 450191-S (II)

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