Novel acylethanolamide derivatives that modulate body weight through enhancement of hypothalamic pro-opiomelanocortin (POMC) and/or decreased neuropeptide y (NPY)

Yosefa Avraham*, Jehoshua Katzhendler, Lia Vorobeiv, Shira Merchavia, Chana Listman, Eithan Kunkes, Fida' Harfoush, Sawsan Salameh, Aviva F. Ezra, Nikolaos C. Grigoriadis, Elliot M. Berry, Yousef Najajreh

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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, PPARα, 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.

Original languageEnglish
Pages (from-to)1811-1829
Number of pages19
JournalJournal of Medicinal Chemistry
Volume56
Issue number5
DOIs
StatePublished - 14 Mar 2013

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