Benzofuran Derivatives Inhibit 11β-Hydroxysteroid Dehydrogenase Type 1 Activity in Rat Adipose Tissue
| Autor: | Yuko Yamaguchi, Midori Wakabayashi, Toshiaki Kogure, Yoshiharu Kobayashi, Daisuke Kiyonaga, Noriko Tagawa, Masafumi Ueda, Okiko Miyata |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty Pharmaceutical Science Adipose tissue Intra-Abdominal Fat Mice chemistry.chemical_compound Metabolic Diseases Corticosterone 11β-hydroxysteroid dehydrogenase type 1 3T3-L1 Cells Microsomes Internal medicine Adipocyte 11-beta-Hydroxysteroid Dehydrogenase Type 1 medicine Animals Mesentery Obesity Rats Wistar Benzofuran Benzofurans Pharmacology Dose-Response Relationship Drug biology Biological activity General Medicine Rats Endocrinology chemistry biology.protein Microsome NADP hormones hormone substitutes and hormone antagonists Glucocorticoid medicine.drug |
| Zdroj: | Biological and Pharmaceutical Bulletin. 35:1275-1280 |
| ISSN: | 1347-5215 0918-6158 |
| Popis: | Excess glucocorticoids promote visceral obesity and insulin resistance. The main regulator of intracellular glucocorticoid levels are 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive glucocorticoid into bioactive glucocorticoid such as cortisol in humans and corticosterone in rodents; therefore, the inhibition of 11β-HSD1 has considerable therapeutic potential for metabolic diseases including obesity and diabetes. Benzofuran is a key structure in many biologically active compounds such as benzbromarone, malibatol A and (+)-liphagal. The aim of this study was to investigate the inhibitory effect of benzofuran derivatives on 11β-HSD1 in mesenteric adipose tissue from rodents. 11β-HSD1 activity was determined by incubation of rat mesenteric adipose tissue microsomes in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) with and without benzofuran derivatives (Compounds 1-14). The corticosterone produced was measured by HPLC. More than 40% of 11β-HSD1 inhibition was observed in Compounds 1, 5, 7 and 8. Moreover, Compounds 7 and 8 inhibited the 11β-HSD1 activity in adipose microsomes dose- and time-dependently, as well as in 3T3-L1 adipocytes. Compounds 7 and 8 did not inhibit 11β-HSD type 2 (11β-HSD2), whereas Compounds 1 and 5 inhibited 11β-HSD2 by 18.7% and 56.3%, respectively. Further, a kinetic study revealed that Compounds 7 and 8 acted as non-competitive inhibitors of 11β-HSD1. Ki (nmol/h/mg protein) values of Compounds 7 and 8 were 17.5 and 24.0, respectively, with IC50 (µM) of 10.2 and 25.6, respectively. These data indicate that Compounds 7 and 8 are convincing candidates for seed compounds as specific inhibitors of 11β-HSD1 and have the potential to be developed as anti-obesity drugs. |
| Databáze: | OpenAIRE |
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