Anxiolytic-like effects of 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate in mice

Abstract

The pharmacological effects of 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate (PTMB), a novel synthetic benzodiazepine, were examined in mice. In the elevated plus-maze test of anxiety, 0.3-1 mg/kg diazepam ip (F(3,53) = 3.78; P<0.05) and 1-10 mg/kg PTMB ip increased (F(5,98) = 3.26; P<0.01), whereas 2 mg/kg picrotoxin ip decreased (F(3,59) = 8.32; P<0.001) the proportion of time spent in the open arms, consistent with an anxiolytic action of both benzodiazepines, and an anxiogenic role for picrotoxin. In the holeboard, 1.0 mg/kg diazepam ip increased (F(3,54) = 2.78; P<0.05) and 2 mg/kg picrotoxin ip decreased (F(3,59) = 4.69; P<0.01) locomotor activity. Rotarod assessment revealed that 1 mg/kg diazepam ip and 3, 10 and 30 mg/kg PTMB ip produced significant motor incoordination compared to vehicle control (F(4,70) = 7.6; P<0.001). These data suggest that the recently synthesized PTMB compound possesses anxiolytic activity and produces motor incoordination similar to those observed with diazepam. PicrotoxinBenzodiazepine compounds have been reported to be the most extensively consumed psychoactive drugs worldwide due to their anxiolytic and anticonvulsant activity. However, undesirable side effects like muscle relaxation, sedation, physical dependence, tolerance, ataxia and memory impairment have been associated with the use of benzodiazepines. A variety of novel agents capable of interacting with benzodiazepine receptors have been investigated in order to develop non-sedative anxioselective agents (1-3). Two main hypotheses for the development of such anxioselective drugs have been proposed. The first suggests that different benzodiazepine receptor subtypes may be responsible for the behavioral effects of benzodiazepine compounds. According to this hypothesis, two receptor subtypes, benzodiazepine (omega) 1 and benzodiazepine (omega) 2 receptors, exist in different brain areas responsible for different physiological functions (2). The alternative hypothesis proposes the development of benzodiazepine receptor partial agonists which present lower intrinsic efficacy sufficient to maintain the anxiolytic and anticonvulsant responses, but insufficient to induce the side effects seen with full agonists (2,4). Most of the benzodiazepines used in clinical therapeutics are 1,4-benzodiazepines (5-7), since several products were generated by introducing substituents at different positions of the benzodiazepine ring of diazepam. Modifications in the structure of the ring have also been made, and the anxiolytic effect of 1,5-benzodiazepines (clobazam) has been described (8,9). However, considerably less is known about the effects of substituents on 1,5-benzodiazepines compared to the 1,4 group. In the present study we investigated the anxiolytic potential of the recently synthesized 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate (PTMB) (10). The effects of this new benzodiazepine on spontaneous coordinated motor movements were also evaluated.Male albino mice (35-40 g) from our ...

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“…Anxiolytic-like behavior was evaluated using the task of the elevated plus maze, as previously described (Frussa-Filho et al, 1999;Rubin et al, 2000a). The apparatus consists of a wooden structure raised to 50 cm from the floor.…”

Antinociceptive effect of novel pyrazolines in mice

“…Five minutes after the measurement of tail withdrawal (35 min after sc injection of vehicle or pyrazolines), each mouse was tested in the rotarod. The latency to fall, as well as the number of falls from the apparatus, were recorded with a stopwatch up to 240 s (19)(20)(21).…”

Regiospecific synthesis of 3H‐pyrido[2,3‐b][1,4]diazepin‐4(5H)‐ones viahaloform reaction with the isolation of N3‐[3‐oxo‐4,4,4‐trichloroalk‐1‐en‐1‐yl]‐2,3‐diaminopyridine intermediates

“…On the other hand, over the last few years, we have reported the synthesis of 2‐trifluoro‐ and 2‐trichloromethyl‐3 H ‐1,5‐benzodiazepines from the reaction of 4‐aryl‐4‐methoxy‐1,1,1‐haloalk‐3‐en‐2‐ones with o ‐phenylenediamine in good yields [8]. Next, we demonstrated that 4‐phenyl‐2‐trichloromethyl‐3 H ‐1,5‐benzodiazepine hydrogen sulfate possesses anxiolytic activity and produces motor in co‐ordination similar to that observed in mice given diazepam [9]. In the same year, we also reported that some 4‐substituted 2‐trichloromethyl‐3 H ‐1,5‐benzodiazepines presented an inhibitory effect on acetylcholinesterase and ATPDase activities from cerebral cortex of adult rats [10].…”