Novel Acylethanolamide Derivatives That Modulate Body Weight through Enhancement of Hypothalamic Pro-Opiomelanocortin (POMC) and/or Decreased Neuropeptide Y (NPY)

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• 作者：Yosefa Avraham ; Jehoshua Katzhendler ; Lia Vorobeiv ; Shira Merchavia ; Chana Listman ; Eithan Kunkes ; Fida鈥?Harfoush ; Sawsan Salameh ; Aviva F. Ezra ; Nikolaos C. Grigoriadis ; Elliot M. Berry ; Yousef Najajreh
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：1811-1829
• 全文大小：691K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

Newly synthesized acylethanolamide derivatives oleoyl-l-valinolamide (1), oleoyl-d-valinolamide (2), elaidoyl-l-valinolamide (3), elaidoyl-d-valinolamide (4) stearoyl-l-valinolamide (5), and palmitoyl-l-valinolamide (6) were investigated in mice as antiobesity compounds. Compounds 1, 2, 5, 6 significantly decreased body weight by 6.57% following eight injections of 1 mg/kg ip during 39 days, while 3 and 4 showed no such activity. Receptor binding indicated that no compound activated CB1, CB2, PPAR伪, or TRPV1 receptors. Hypothalamic RT-PCR showed that mRNA expression of the anorexigenic genes POMC and CART was up-regulated by 1, 2, 5 and 1, 2, respectively, while that of the orexigenic genes NPY and CaMKK2 was down-regulated by the respective compounds 1, 5, 6 and 1, 2, 5. Oleoyl-l-valinolamide enhances anorectic pathways and lead to decreased glucose levels, enhanced locomotor activity, and improved cognition. Effects of oleoyl-l-valinolamide on weight were dose-dependent, and it could be given orally. 1, 2, 4, 5 down-regulated FAAH mRNA expression.