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We report the synthesis, antioxidant and antiproliferative activity and a QSAR analysis of synthetic diphenylpropionamide derivatives. Synthesis of these compounds was achieved by direct condensation of 2,2- and 3,3-diphenylpropionic acid and appropriate amines using 1-propylphoshonic acid cyclic anhydride (PPAA) as catalyst. Compound structures were elucidated by NMR analysis and their melting points were measured. The in vitro antioxidant activity of these compounds was tested by evaluating the amount of scavenged ABTS radical and estimating ROS and NO production in LPS stimulated J774.A1 macrophages. All compounds were tested for their effect on viability of cells and results demonstrated that they are not toxic towards the cell lines used. The cytotoxic activity of all compounds was evaluated by a Brine Shrimp Test.

The presence and function of CB 2 receptors in central nervous system (CNS) neurons are controversial. We report the expression of CB 2 receptor messenger RNA and protein localization on brainstem neurons. These functional CB 2 receptors in the brainstem were activated by a CB 2 receptor agonist, 2-arachidonoylglycerol, and by elevated endogenous levels of endocannabinoids, which also act at CB 1 receptors. CB 2 receptors represent an alternative site of action of endocannabinoids that opens the possibility of nonpsychotropic therapeutic interventions using enhanced endocannabinoid levels in localized brain areas.

In the present study, 11 novel N -(3,3-diphenyl)propyl-2,2-diphenylacetamide derivatives ( 4a – d and 9a – g ) and six triphenylacetamides ( 10a – c and 11a – c ) were synthesized and tested as ligands of cannabinoid CB 1 and CB 2 receptors. All compounds exhibited affinity for CB 1 and CB 2 receptors. Four compounds ( 4b , 9a , 9b , and 11a ) showed selectivity for CB 1 versus CB 2 receptors, although only the N -(3,3-diphenyl)propyl-2,2-diphenylacetamide ( 4b ) can be considered a potent CB 1 ligand ( K i = 58 nM). It was 140-fold selective over CB 2 receptors ( K i = 7800 nM) and behaved as an inverse agonist by stimulating forskolin-induced cAMP formation in mouse N18TG2 neuroblastoma cells. This compound is the first of a novel class of tetraphenyl CB 1 ligands that, in view of its easy synthesis and high affinity for CB 1 receptors and despite its sterical hindrance, will be useful for the design of new blockers of this therapeutically exploitable receptor type.

The present study was designed to examine whether arvanil (N-arachidonoyl-vanillyl-amide), an endocannabinoid/vanilloid structural “hybrid”, might provide symptom relief in the rat model of Huntington's disease (HD) generated by bilateral intrastriatal application of 3-nitropropionic acid (3-NP), where previous evidence suggests that hybrid cannabinoid/vanilloid compounds might be effective. As expected, arvanil did reduce ambulation, stereotypic activity, and number of hole entries, and increased the inactivity, in control rats. It was also active in 3-NP-lesioned rats, where, despite its lowering effects on stereotypic activity and number of hole entries, arvanil reduced the hyperkinesia (increased ambulation) typical of these rats, and also increased the inactivity, these two effects being more moderate than those found in control rats. Arvanil caused its antihyperkinetic effects in 3-NP-lesioned rats presumably by enhancing excitatory transmission at the globus pallidus, since it increased glutamate content in this region. This contrasts with its effects in control rats where arvanil enhanced GABA transmission at the globus pallidus. In summary, arvanil does alleviate hyperkinesia typical of HD, although it also affects locomotion in normal rats. Nevertheless, considering the lack of efficacious pharmacological treatments in this basal ganglia disorder, our findings might provide the basis for the development of more specific drugs against HD.