Analgesic and anti-inflammatory activities of certain 6-aryl-9-substituted-6,9-diazaspiro-[4,5]decane-8,10-diones in mice | ||||
| Egyptian Pharmaceutical Journal | ||||
| Volume 14, Issue 3, September 2015, Page 196-203 PDF (593.67 K) | ||||
| DOI: 10.4103/1687-4315.172877 | ||||
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| Authors | ||||
| Mona E. Aboutabl; Walaa H.A. Abd El-Hamid | ||||
| Abstract | ||||
| Background and objective 2,6-Diketopiperazines are promising bioactive chemical entities in drug discovery. They could be considered a versatile template for the synthesis of a variety of scaffolds because of the presence of the reactive endocyclic nucleophilic imide group. It is worth mentioning that the 2,6-diketopiperazine system is embedded in the chemical skeleton of 6,9-diazaspiro-[4,5] decane-8,10-diones. The aim of the present work was to study both peripheral and central analgesic activities as well as the anti-inflammatory activity of 6-aryl-9-substituted-6,9-diazaspiro-[4,5]decane-8,10-diones 1–9 in different in-vivo experimental models. Materials and methods The test compounds 1–9 were evaluated for their analgesic activity in adult male Swiss albino mice using the writhing (12.5 and 25 mg/kg) and hot-plate (25 mg/kg) tests. Moreover, the anti-inflammatory activity was assessed for compounds 1–9 at dose 25 mg/kg (0.066–0.079 mmol/kg) by intraperitoneal administration using carrageenan-induced hind-paw edema assay in mice at 1, 2, and 3 h after carrageenan challenge and compared with diclofenac sodium at dose 10 mg/kg (0.031 mmol/kg) as the reference drug. Results and conclusion All compounds 1–9 showed significant inhibition of acetic acid induced writhing in the writhing test. Their percentage inhibition of abdominal writhing induced by acetic acid (peripheral effect) at doses of 12.5 mg/kg (0.033–0.039 mmol/kg) and 25 mg/kg (0.066–0.079 mmol/kg) ranged from 68.55 to 17.74% and from 88.71 to 53.23%, respectively. Compound 7 (R = H, R = CHCHPh) demonstrated the highest writhing inhibition percentage at both dose levels (88.71 and 68.55%, respectively) and exhibited significantly lower number of writhes compared with diclofenac sodium as the reference standard. In the hot-plate test (central effect), compounds 2 (R = CH, R = CHCOOH) and 3 (R = 4-OCH, R = CHCOOCH) at doses of 0.076 and 0.072 mmol/kg, respectively (equivalent to 25 mg/kg), significantly raised the pain threshold and exhibited the best analgesic activity at 30 min. Both of them displayed nonsignificant difference from tramadol hydrochloride (0.095 mmol/kg, 25 mg/kg) at 30 min. In contrast, compounds 1 (R = H, R = CHCOOH) at dose 0.079 mmol/kg and 5 (R = CH, R = CHPh) at dose 0.068 mmol/kg showed slight lower analgesic potency compared with 2 and 3 with significant difference from the reference drug. The most powerful anti-inflammatory effect in this series was demonstrated in 9--methyl acetate derivatives (1–3), where compound 1 (R = H, R = CHCOOH) at dose 0.079 mmol/kg exhibited 53.93% maximum protection (inhibition of edema size) at 3 h, compared with diclofenac sodium (0.0314 mmol/kg), which reached 60.40%. On the other hand, compounds 4–9 displayed 36.90–26.77% protection against carrageenan-induced edema. | ||||
| Keywords | ||||
| analgesic; Anti-inflammatory; 2,6-diketopiperazines; 6,9-diazaspiro-[4,5]decane-8; 10-diones; hot-plate; writhing | ||||
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