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 i.p. 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.

No abstract

Introduction – The obesity pandemic is multifactorial. Nutritional, pharmacologic and surgical interventions are limited in reach and efficacy, raising need for new therapeutics.Aims – Characterization of anorexigenic and cognitive effect and central mechanism of action of novel N‐acylethanolamide derivatives.Methods – Sabra mice divided to similar experimental groups, injected IP with: oleyl‐L‐leucinolamide (1 A), linoleyl‐L‐leucinolamide (4 A), linoleyl‐L‐valinolamide (5 A), oleyl‐oxycarbonyl‐L‐valinolamide (1 B), oleyl‐oxycarbonyl‐D‐valinolamide (2 B), oleylamine‐carbonyl‐L‐valinolamide (3 B), oleylamine‐carbonyl‐D‐valinolamide (4 B), and oleyl‐L‐hydroxyvalineamide (5 B). Control group with vehicle. Body weight and food consumption followed for 39 days. Motor activity and cognitive function by open field test and eight‐arm maze. Mice sacrificed and mechanism of action investigated by qPCR. The genes analyzed involved in energy balance and regulation of appetite. Catecholamines and serotonin evaluated.Results – Compounds 1 A, 5 A, 1 B–4 B, caused significant weight loss of 4.2–5.6 % and 5 A, 1 B–4 B, improved cognitive function following 8 i. p. injections of 1 mg/kg during 39 days, by different mechanisms. 5 A, 3 B and 4 B decreased food consumption, whereas 1 A, 5 A and 2 B increased motor activity. 1 A, 4 A, 1 B and 3 B elevated SIRT‐1, associated with survival. POMC upregulated by 1 B and 2 B, CART by 1 B, 2 B and 1 A. NPY and CAMKK2 downregulated by 5 A. 4 B enhanced 5‐HT levels. 4 A, 5 A, 1 B, 4 B, 5 B decreased FAAH, showing long lasting effect.Conclusions – These new compounds might be developed for the treatment of obesity and for improved cognitive function.