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A Novel Peripheral CB1 Antagonist and Its Effect on Metabolic Parameters
Author(s) -
Hung MingShiu,
Vijayakumar Ramasamy S.,
Lin Yinchiu,
Chang ChunPing,
Yeh YenNan,
Hsiao Wenchi,
Chao YuSheng,
Shia KakShan
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.lb428
Subject(s) - cannabinoid receptor , rimonabant , cannabinoid , chemistry , receptor , antagonist , lipolysis , endocrinology , endocannabinoid system , medicine , postprandial , agonist , hypothermia , pharmacology , appetite , adipose tissue , biochemistry , insulin
Activation of cannabinoid receptor 1 (CB1), a G protein‐coupled receptor, mediates a positive energy balance by decreasing the energy expenditure, meanwhile enhances appetite and anabolic pathways via both central and peripheral actions. As the function of CB1 receptor favors the energy influx and antagonization of its physiological effect becomes a potential therapeutic target for treating obesity and metabolic diseases. However, prior studies have indicated the psychological side effects resulted from the central action of CB1 receptors, which limits the development of centrally acting CB1 antagonists. Thereof, identification of peripheral CB1 compounds is actively pursued. Compound 1 (IC 50 = 25.8 nM, EC50 = 89.8 nM) is an orally active aryl alkynylthiophene analog. While administered at 20 mg/kg, it exhibited a unique profile with significant weight loss but failed to suppress food intake in rats. Very low brain/plasma (0.04) ratio of this compound denoted that it is less permeable to brain tissue. In addition, compound 1 at a dose as high as 50 mg/kg did not reverse CB1 agonist‐induced hypothermia and analgesia in mice, thus discriminated the central CB1‐dependent effects. Furthermore, compound 1 treatment to postprandial rats increased the level of plasma free fatty acids and ketone bodies which accompanied elevated rate of lipolysis and lipid oxidation. These results suggest that compound 1 is a peripheral acting CB1 antagonist and can be served as a promising lead compound for later drug development.