Design, synthesis and anticonvulsant activity of 2-[2-Phenoxy] phenyl-1,3,4-oxadiazole derivatives

Benzodiazepines are useful drugs for treatment of sleep disorders, anxiety, seizure cases and skeletal muscle cramps. Some derivatives of 2-[2-Phenoxy] phenyl-1, 3, 4-oxadiazole were synthesized as benzodiazepine receptor agonists. Conformational analysis and superimposition of energy minima conformers of the compounds on estazolam, a known benzodiazepine agonist, reveal that the main proposed benzodiazepine pharmacophores were well matched. Anticonvulsant activity of the synthesized compounds, determined by pentylenetetrazole-induced lethal convulsion test, showed that the introduction of an amino substituent in position 5 of 1, 3, and 4 - oxadiazole ring generates compound 9 which has a respectable effect. The results are in agreement with SAR of benzodiazepine receptor ligands since the elimination of electronegative substituent in position 2 of phenoxy ring or position 4 of phenyl ring reduces the anticonvulsant activity

Involvement of the nucleus accumbensshell presynaptic NMDA receptors on anxiolytic-like behaviors induced by NMDA in adult male Wistar rat

Glutamatergic system stimulationthe nucleus accumbens shell, may affect anxiety-related behaviors, aversive learning and memory. Glutamate receptors are differentially distributed in pre- and postsynaptic sites contributing to neuronal communications.The present study aimed to examine the possible involvement of the NAc shell presynaptic NMDA receptors on NMDA induced responses, using the elevated-plus maze [EPM] task in maleWistar rats. Bilateral guide cannulae were implanted to allow microinjection of glutamatergic agonist [NMDA] or ca+2 channel blocker [SKF96365 hydrochloride] agents. Pretest intra-NAc shell infusion of NMDA induced anxiolytic-like behaviors and impaired the EPM-associated memory upon test and retest, respectively. In addition our findings showed that, the intra-NAc shell infusion of Ca+2 channel blocker at applied doses, does not alter the anxiety-like response and aversive memory upon test and retest, respectively. Furthermore, infusing the subthreshold dose SKF prior to the injection of effective doses of NMDA, reduced the anxiolytic-like response and improved the aversive memory impairment which had already been induced by intra-NAc shell NMDA injection. Our study showed that,inhibition of the neurotransmitter exocytosis from pre-synaptic neuron via Ca+2 channel blockade bySKF96365 decreases affected induced by NMDA in the NAc shell region, indicating the involvement of the pre-synaptic NMDA receptors in NMDA induced responses.Therefore, NMDA's ability to increase anxiolytic-like behaviors and the aversive memory impairment may be the result of an action on pre-synaptic glutamatergic receptors which in turn decrease the glutamate effect at synaptic terminal level

Influence of nitric oxide in the central amygdala on the acquisition and expression of morphine-induced place preference in morphine sensitized rats

Effects of intra-central amygdala administration of L-arginine, a nitric oxide precursor, and NG-nitro-L-arginine methyl-ester [L NAME], a nitric oxide synthase inhibitor, on the morphine-induced sensitization and also on the expression of morphine-induced place conditioning in rats were studied. Subcutaneous [s.c.] administration of morphine [2.5, 5 and 7.5 mg/kg] induced place conditioning. Repeated pretreatment of morphine [5 mg/kg, i.p.] followed by 5 days no drug treatment, increased place conditioning induced by morphine [0.5 mg/kg]. Repeated intra-central amygdala administration of L-arginine [0.3, 1 and 3 µg/ rat], with morphine during acquisition of sensitization, significantly increased or reduced morphine place conditioning in sensitized rats. The drug administration before testing also increased and reduced the expression of morphine place conditioning in sensitized animals. Repeated intra-central amygdala injections of L-NAME [0.3, 1 and 3 µg/rat] with morphine during acquisition of sensitization, reduced the acquisition of morphine place conditioning in the sensitized animals. The drug injection before testing also reduced morphine induced conditioning. The results indicate that nitric oxide [NO] within the central amygdala may be involved in the acquisition and expression of morphine place conditioning in morphine-sensitized rats