Anandamide analogs, studies

To further explore the question of the mechanism of anandamide amidase inhibition, analogs of anandamide were synthesized (Koutek et al. 1994). These anandamide analogs (figure 6) represent three classes of putative transition-state inhibitors trifluoromethyl ketone (4), -keto ester (3), and -keto amide derivatives (2). The general strategy of this study was based upon the h q)othesis that polarized carbonyls, such as those in trifluoromethyl ketones and -keto carboxylate derivatives, may form stabilized hydrates or enzyme adducts that mimic the tetrahedral... 

Two subtypes of G protein-coupled receptors for cannabis s psychotropic component, A -tetrahydrocannabinol (THC), have been cloned to date, the cannabinoid CBi and CB2 receptors (Howlett et al. 2004). Yet, five different types of endogenous agonists for these cannabinoid receptors have been identified so far (Fig. 1). These compounds, named endocannabinoids by analogy with THC (Di Marzo and Fontana 1995), are all derived from long-chain polyunsaturated fatty acids. In particular (1) the anandamides are amides of ethanolamine with polyunsaturated fatty acids with at least 20 carbon atoms and three 1,4-diene double bonds. The C20 4 homologue in this series, V-arachidonoylethanolamine (AEA) (Devane et al. 1992), also known simply as anandamide, has been most studied. 

Thomas et al. were first to report a CoMFA QSAR pharmacophore model for anandamide (4) audits analogs (Thomas etal. 1996). These authors used molecular dynamics studies to explore conformations of 4 that present pharmacophoric similaritieswith2l -THC(l). A J-shaped or looped conformation of 4 was identified that had good molecular volume overlap with 1 when (1) the carboxyamide of 4 was overlaid with the pyran oxygen (0-5) in 1 (2) the head group hydroxyl of 4 was overlaid with the C-1 phenolic hydroxyl group of 1, (3) the five terminal carbons of the 4 fatty acid acyl chain were overlaid with the C-3 pentyl side chain of 1 and... 

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