Acyl chain SAR

Acyl Chain SAR Fatty Acid Ethanolamides Effect of Unsaturation... 

Acyl chain SAR resnlts also indicate that a minimum of live carbons must be present in the satnrated, terminal region of the acyl chain, and that a minimum of 20 carbons in the acyl chain are reqnired for binding to the catmabinoid CB, receptor. It is difficult to reconcile these requirements based solely on conformational mobility yet any pharmacophore for AEA interaction with CBj shonld be able to accoimt for these two requirements as well. Hypotheses concerning the origin of these two SAR reqnirements are discussed in the section titled Pharmacophore for Endocannabinoid Interaction with Catmabinoid Receptors later in this chapter. 

Endocannabinoid SAR indicates that the CBi receptor recognizes ethanolamides whose fatty acid acyl chains have 20 or 22 carbons, with at least three homoallylic... 

Endocannabinoid SAR at the CB receptors can be divided into studies of head group- and acyl chain requirements for high-affinity binding. 

Pravachol is a 6 J-hydroxy acid form of compactin and can be produced by microbial transformation [32], Pharmacologically, the active form of mevinolin is the p-hydroxyacid form the lactone form is inactive. Chemical modification of the ester side chain revealed that its stereochemistry was not important but acyl moiety was essential. Removal of the side chain or side chain ether analogues resulted in marked loss of potency [33]. Extensive SAR studies have led to the development of simvastatin, a 2,2-dimethylbutyrate derivative of mevinolin. Simvastatin, with the dissociation constant Ki of 0.2 nM, is about 3 times more potent than mevinolin and 11 times than pravachol and has been clinically proven to be more effective than either mevinolin or pravachol. 

GC analysis of the methyl esters gives the alkyl chain length distribution of the acyl sar-cosines and of free fatty acids. The sample is first acidified and extracted with n-hexane or petroleum ether to isolate the acylsarcosinate and soap in the form of the free carboxylic acids. About 1 g of the acids are reacted with 25 mL methanol and 2 drops of concentrated sulfuric hours for 2 hr under reflux to form the methyl esters. These are isolated by adding 75 mL saturated aqueous NaCl and extracting with 25 mL -hexane. The hexane phase is washed with saturated NaCl until neutral and evaporated down. (If an emulsion forms, a... 

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