Anandamide analogs

Padgett, L. W., Howlett, A. C., Shim, J. Y. (2008) Binding mode prediction of con-formationally restricted anandamide analogs within the CB1 receptor. J Mol Signal 3, 5. 

Anandamide was isolated from water-insoluble fractions of the porcine brain. It binds to CB1 with rather moderate affinity (Ki 61 nM) and a low affinity for the CB2 receptor (Ki 1930 nM). The name anandamide is based on its chemical nature (an amide) and the Sanskrit word ananda meaning bliss. The chemical structure of anandamide can be divided into two major molecular fragments a polar ethanolamido head group and a hydrophobic arachidonyl chain. The polar head group comprises a secondary amide functionality with an N-hydroxyalkyl substituent while the lipophilic fragment is a non-conjugated c/ s tetraolefinic chain and an n-pentyl chain reminiscent of the lipophilic side chain found in the classical cannabinoids. A number of anandamide analogs have been synthesized and demonstrated to have considerable selectivity for the CB1 receptor in comparison to the CB2 receptor. 

Pate, D.W. Jarvinen, T. Jarvinen, K. Urtti, A. Anandamide Analog Compositions and Method of Treating Intraocular Hypertension Using Same 1999 US 5,977,180... 

Soon after the discovery of anandamide, enzymatic activities responsible for its degradation (an amidase, also called an amidohydrolase) and s mthesis (synthase) were described (DiMarzo et al. 1994 Desamaud et al. 1995 Ueda et al. 1995 Deutsch and Chin 1993 Kruszka and Gross 1994 Devane and Axelrod 1994). Phenylmethylsulfonyl fluoride (PMSF) was discovered to be a potent inhibitor of the enzymatic breakdown of arachidonoylethanolamide (Deutsch and Chin 1993). A series of anandamide analogs was synthesized (trifluoromethyl ketone, -keto ester, and -keto amide derivatives) and tested in vitro and in intact cells as amidase inhibitors (Koutek et al. 1994). The trifluoromethyl ketones (e.g., arachidonyltrifluoromethyl ketone) were found to be potent inhibitors in the low micromolar (M) range. Most recently, a potent irreversible inhibitor of anandamide hydrolysis (AM 374) has... 

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... 

Adams IB, Ryan W, Singer M, Thomas BF, Compton DR, Razdan RK, Martin BR (1995) Evaluation of cannabinoid receptor binding and in vivo activities for anandamide analogs. J Pharmacol Exp Ther 273 1172-1181... 

Ryan WJ, Banner WK, WUey JL, Martin BR, Razdan RK (1997) Potent anandamide analogs the effect of changing the length and branching of the end pentyl chain. J Med Chem 40 3617-3625... 

Thomas BF, Adams IB, Mascarella SW, Martin BR, Razdan RK (1996) Structure-activity analysis of anandamide analogs relationship to a cannabinoid pharmacophore. J Med Chem 39 471-479... 

Although initially it seemed that the development of rigid anandamide analogs that mimic the AA conformations discussed above would help to identify the receptor-appropriate conformation of AEA, all attempts at rigidifying AEA have... 

Despite the fact that the endocannabinoid transporter has not yet been isolated or cloned, a situation that has led to some controversy about its existence (Glaser et al. 2003), there are several anandamide analogs that behave in vitro as endocannabinoid transport inhibitors (Giuffrida et al. 2001) and that, in vivo, produce significant effects on motor function (for review see Ferndndez-Ruiz et al. 2002). 

Although there is very little structural similarity between the classical cannabinoids and anandamide, there is considerable evidence suggesting that these two classes of cannabimimetic agents bind similarly to the CBi-active site (87). It was thus assumed that incorporation of the l, l -dimethylalkyl side chain (from classical cannabinoids) in AEA structure would lead to potent analogs. Indeed, tail-chain-modified anandamide analogs (73,74, Fig. 10) bearing a dimethylalkyl chain exhibited marked increases in receptor affinities and in vivo potencies (88-90). 

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