Analgesic and anti-inflammatory activities of certain 6-aryl-9-substituted-6,9-diazaspiro-[4,5]decane-8,10-diones in mice

Abstract

Background and objective2,6-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 methodsThe 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 conclusionAll 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 1 = H, R 2 = CH 2 CH 2 Ph) 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 1 = CH 3 , R 2 = CH 2 COOH 3 ) and 3 (R 1 = 4-OCH 3 , R 2 = CH 2 COOCH 3 ) 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 1 = H, R 2 = CH 2 COOH 3 ) at dose 0.079 mmol/kg and 5 (R 1 = CH 3 , R 2 = CH 2 Ph) 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-N-methyl acetate derivatives (1-3), where compound 1 (R 1 = H, R 2 = CH 2 COOH 3 ) 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.