Benzodiazepines (BZD) are among the main classes of tranquilizing drugs, bearing much less toxicity compared to other drugs acting on the CNS. Considering the pharmacophore model of BZD binding to GABA-A receptor, novel diphenyl 1,3,4-oxadiazole compounds as BZD ligands were designed. The compounds were synthesized and structurally confirmed using LCMS, IR and NMR techniques. We investigated the affinity of the compounds to BZD receptors using radioligand [3H]-flumazenil by in-vitro studies. In addition, sedative-hypnotic, anxiety, anticonvulsant, muscle relaxant, memory impairment, and motor coordination activities of the synthesized compounds were evaluated using in-vivo studies. Based on in-vitro studies, compounds 7i and 7j were the most potent with IC50 values of 1.54 and 1.66 nM respectively. In-vivo studies showed that compound 7i has the highest impact on increased sedation, muscle relaxation, and decreased anxiety and these observations were antagonized by flumazenil. Compounds 7e and 7i were the most potent anticonvulsant agents among synthesized compounds in both MES and PTZ induced seizure tests. All synthesized compounds significantly decreased latency to fall in the Rotarod test but none of them had a significant impact on the memory impairment test.
The aim of current study was evaluating the frequency of clopidogrel resistance and its impact on clinical outcome of patients in Iranian patients. Patients undergoing percutaneous coronary intervention in Imam Hussein Medical center, Tehran, Iran, who received standard dosage of clopidogrel (Plavix®, Sanofi, France, 600 mg loading dose and 75 mg/day afterward) were recruited. Platelet aggregation was measured using light transmission aggregometer. The patients were categorized as responder (platelet aggregation less than 43%) and non-responder (platelet aggregation more than 43%). All patients were evaluated for major adverse cardio vascular events one month and 3 years after the angioplasty based on MACE criteria by phone contact. One hundred and five patients with average age of 60.30 ± 12.2 years entered the study of whom 26 (24.76%) did not respond to clopidogrel. None of patients experienced cardiac events one month after PCI. Three years after PCI, data were collected from 55 (69.62%) and 10 (38.46%) subjects in responder and non-responder groups, respectively. MACE criteria was positive in 4 patients, 3 (5.45%) in responder and 1 (10%) in non-responder group (p = 0.28). We did not find any significant differences between clopidogrel resistance and past medical history. In drug history 1 (1.26%) and 4 (15.38%) patients received omeprazole with clopidogrel in responder and none-responder group, respectively (p = 0.003). This study showed 24.76% resistance to clopidogrel in Iranian population but, we did not find any correlation between clopidogrel resistance and cardiac events in follow up maybe due to study limitations particularly missed follow-up in non-responder patients.
