Synthesis and Influence of Two Quinoxalinone Derivatives on Anxiety- and Depressive-Like Responses in Wistar Rat

Abstract

Background: Anxiety and depression seem to be associated with modification in central neurotransmission deterioration of monoaminergic systems (norepinephrine: NA, dopamine: DA and serotonin: 5HT). The use of antidepressants like clomipramine (CLMP), an inhibitor of 5HT uptake and anxiolytics like diazepam (DZ), a potentialisator of the GABAergic transmission, seems effective to cure these syndromes. Though, Benzodiazepines (Bzs) are well-established, clinically useful anxiolytics, but some effects that are characteristic of these drugs, particularly sedation and muscle relaxation, have been considered unwanted side effects. The goal of this study was to test the hypothesis that subchronic administration of quinoxalinic compounds would induce significant behavioural changes in Wistar rats. Methods: For this purpose, two new quinoxalinic derivatives (2 (1H)-quinoxalinone and 6 -nitro-2 (1H)-quinoxalinone) have been synthesized adopting Hong method (Hong 2000) and investigated for some neuropharmacological effects (anxiety- and depressive-like responses) in rats. The present experiment sought to determine whether treatment with the compounds produces changes in affective responses. The rats were daily injected intraperitoneally; the anxiolytic and antidepressant standard group rats were administered with DZ (1mg/kg) or CLMP (2mg/kg) respectively. In the experiment using quinoxalinic derivatives, rats were administered with (6-nitro-2(1H)-quinoxalinone or 2(1H)-quinoxalinone) (30mg/kg). Appropriate control studies were performed administering vehicle in place of drug. After two weeks in treatment conditions, the rats underwent a battery of behavioural tests (open field and elevated plus maze) to measure anxiety- and (forced swimming test) to measure depressive-like responses. To eliminate any lingering olfactory cues, the pieces of test equipment were thoroughly cleaned by using water and 20% alcohol followed by thorough drying before each rat was tested. Data are expressed as the means + standard error of the means (S.E.M.). To determine the differences between experimental groups statistical analysis was performed by analysis of variance (ANOVA) 1st order followed by a post-hoc tests (Fisher LSD) or Student test "t". Intergroup differences were considered significant when p < 0.05, very significant when p < 0.01 and highly significant at p < 0.001. Results: The results indicate that the sub-chronic injection of 6-nitro-2(1H)-quinoxalinone showed obvious anxiolytic and antidepressant effects, respectively, measured in the behavioral tests of EPM and FST. The 6-nitro-2(1H)-quinoxalinone showed a comparative anxiolytic effect in rats as Dz and a comparative antidepressant effect as CLMP. The 2(1H)-quinoxalinone significantly reduced depressive-like responses as evaluated in FST, whereas any anxiolytic effect was shown as measured in OF and EPM. Locomotor activity levels in OFT and EPM were unaffected by treatment. Conclusion(s): In conclusion, these data allowed us to make an observation on structure-activity relationships. The results of behavioural tests seem to confirm that for the anxiolytic-like activity, an electron-withdrawing substituent in the benzene moiety is necessary. In fact the compound maintaining the electronwithdrawing group (NO2) in the benzene moiety displayed both anxiolytic- and antidepressive-like effects.