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

被引：13

作者：

Avraham, Yosefa ^{[1
]}

Katzhendler, Jehoshua ^{[2
]}

Vorobeiv, Lia ^{[1
]}

Merchavia, Shira ^{[1
]}

Listman, Chana ^{[1
]}

Kunkes, Eithan ^{[1
]}

Harfoush, Fida' ^{[3
]}

Salameh, Sawsan ^{[3
]}

Ezra, Aviva F. ^{[2
]}

Grigoriadis, Nikolaos C. ^{[4
]}

Berry, Elliot M. ^{[1
]}

Najajreh, Yousef ^{[3
]}

机构：

[1] Hebrew Univ Jerusalem, Fac Med, Braun Sch Publ Hlth, Dept Human Nutr & Metab, IL-91120 Jerusalem, Israel

[2] Hebrew Univ Jerusalem, Fac Med, Sch Pharm, Inst Drug Res, IL-91120 Jerusalem, Israel

[3] Al Quds Univ, Fac Pharm, Anticanc Drugs Res Lab, Jerusalem, Israel

[4] Aristotle Univ Thessaloniki, AHEPA Univ Hosp, Dept Neurol, GR-54006 Thessaloniki, Greece

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 05期

关键词：

CENTRAL-NERVOUS-SYSTEM; N-PALMITOYL-ETHANOLAMINE; FATTY-ACID AMIDE; CANNABINOID RECEPTORS; FOOD-INTAKE; GUT HORMONES; PPAR-ALPHA; ANANDAMIDE; BINDING; OLEOYLETHANOLAMIDE;

D O I：

10.1021/jm300484d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 alpha, 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.

引用

页码：1811 / 1829

页数：19

共 89 条

[1]

ADAMS IB, 1995, J PHARMACOL EXP THER, V273, P1172

[2] Activation of TRPV1 by the satiety factor oleoylethanolamide [J].

Ahern, GP .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (33) :30429-30434

[3]

Ahima RS, 2008, FRONT HORM RES, V36, P182, DOI 10.1159/000115365

[4] Hypothalamic CaMKK2 contributes to the regulation of energy balance [J].

Anderson, Kristin A. ;

Ribar, Thomas J. ;

Lin, Fumin ;

Noeldner, Pamela K. ;

Green, Michelle F. ;

Muehlbauer, Michael J. ;

Witters, Lee A. ;

Kemp, Bruce E. ;

Means, Anthony R. .

CELL METABOLISM, 2008, 7 (05) :377-388

[5] Pharmacological characterization of hydrolysis-resistant analogs of oleoylethanolamide with potent anorexiant properties [J].

Astarita, Giuseppe ;

Di Giacomo, Barbara ;

Gaetani, Silvana ;

Oveisi, Fariba ;

Compton, Timothy R. ;

Rivara, Silvia ;

Tarzia, Giorgio ;

Mor, Marco ;

Piomelli, Daniele .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 318 (02) :563-570

[6] Behavioral and neurochemical alterations caused by diet restriction - The effect of tyrosine administration in mice [J].

Avraham, Y ;

Bonne, O ;

Berry, EM .

BRAIN RESEARCH, 1996, 732 (1-2) :133-144

[7] Capsaicin affects brain function in a model of hepatic encephalopathy associated with fulminant hepatic failure in mice [J].

Avraham, Y. ;

Grigoriadis, N. C. ;

Magen, I. ;

Poutahidis, T. ;

Vorobiav, L. ;

Zolotarev, O. ;

Ilan, Y. ;

Mechoulam, R. ;

Berry, E. M. .

BRITISH JOURNAL OF PHARMACOLOGY, 2009, 158 (03) :896-906

[8]

Avraham Y., 2004, PHARM BIOCH BEHAV, P77675

[9] Cannabinoids and Capsaicin Improve Liver Function Following Thioacetamide-Induced Acute Injury in Mice [J].

Avraham, Yosefa ;

Zolotarev, Olga ;

Grigoriadis, Nikolaos C. ;

Pautahidis, Theofilos ;

Magen, Iddo ;

Vorobiav, Lia ;

Zimmer, Andreas ;

Ilan, Yaron ;

Mechoulam, Raphael ;

Berry, Elliot M. .

AMERICAN JOURNAL OF GASTROENTEROLOGY, 2008, 103 (12) :3047-3056

[10] Fish oil promotes survival and protects against cognitive decline in severely undernourished mice by normalizing satiety signals [J].

Avraham, Yosefa ;

Saidian, Mayer ;

Burston, James J. ;

Mevorach, Raphael ;

Vorobiev, Lia ;

Magen, Iddo ;

Kunkes, Eithan ;

Borges, Beatriz ;

Lichtman, Aron H. ;

Berry, Elliot M. .

JOURNAL OF NUTRITIONAL BIOCHEMISTRY, 2011, 22 (08) :766-776

← 1 2 3 4 5 6 7 8 9 →