Homologues and analogues of palmitoylethanolamide : templates for agents affecting the metabolism of endocannabinoids without direct effects upon cannabinoid receptors

Abstract

The endogenous ligands of cannabinoid receptors (i.e. the endocannabinoids) exhibit multiple interesting pharmacological properties. Unfortunately, these compounds are rapidly inactivated by enzymatic hydrolysis which prevents their effective medical use. The design of inhibitors of the proteins responsible of endocannabinoids degradation is thus a necessary step of the development of endocannabinoids-based therapteutics, and was the main aim of the work. Starting from the template of palmitoylethanolamide (PEA), an endogenous substance related to endocannabinoids devoid of cannabinoid receptors affinity, we demonstrated here that analogues and homologues of palmitoylethanolamide (PEA) constitute a interesting pool of selective agents interfering with the endocannabinoid anandamide (AEA) metabolism. Among the multiple derivatives of PEA which were synthesized, palmitoylcyclohexamide was picked out as a selective inhibitor of AEA transporter in C6 and RBL-2H3 cells. Palmitoylisopropylamide was a mixed inhibitor capable of acting on the same time on FAAH and AEA transporter. Oleoylethylamide, N-(1-oxohexadecyl)glycine mehyl ester and N-(2-acetoxyacetyl)pentadecylamine exhibited selective FAAH inhibition. Lauroylethanolamide was a mixed agent which induced moderate FAAH inhibition and enhancement of VR-1 activation by AEA. Palmitoylmorpholinamide and palmitoyldiethylamide were selective VR-1 activation enhancers that increased VR-1 activation by AEA without affecting FAAH nor AEA transporter. Two analogues of PEA were also distinguished for their selectivity to N-palmitoylethanolamine selective acid amidase (NPAA) which preferentially hydrolyzes PEA. Cyclohexylpalmitate and N-cyclohexanecarbonylpentadecylamine are selective inhibitors of NPAA. The selectivity exhibited by the last has allowed its use as pharmacological tool to distinguish NPAA from FAAH in RBL-1 cells. Our approach allowed the discovery of an antinociceptive agent, namely oleoylethylamide (OEt), effective in normal and neuropathic conditions, and capable of modulating AEA, 2-arachidonoylglycerol (2-AG) and oleoylethanolamide (OEA) endogenous tones without any changes in PEA content. We provided further evidence to the hypothesis that manipulation of endocannabinoid tones in vivo with FAAH inhibitors is possible, and can be used to induce some therapeutically useful cannabimimetic effects, without the adverse effects accompanying exogenous cannabinoids like delta9-THC.Doctorat en sciences (sciences chimiques) (CHIM 3)--UCL, 200