Effects of Conjugation in Acyl Chain

In summary, these results suggest that high-afhnity receptor binding requires high hexibility of the acyl chain, as a minimum of three homoallylic double bonds are necessary for binding to CBi. 

The endocannabinoid acyl chain may need to adopt a folded conformation to interact with CBj, or the endocannabinoid may need to adopt several different conformations in order to reach, be recognized by, and trigger the receptor. Only those analogs with high degrees of eqnihbrinm flexibihty may be able to achieve these conformations easily. 

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. 

Most recently, Jonsson and co-workers (2001) studied homologs and analogs of PEA (21). Oleoylethanolamide at 100 pM showed 64.6 1.5% inhibition of pH] WIN55212-2 binding to hnman CBj receptors expressed on CHO cells. Other componnds had lesser effects at CBj. PEA, palmitoylisopropylamide, and R-palmitoyl-(2-methyl)ethanolamide had modest effects npon pH] CP55940 binding to hnman CB, receptors expressed on CHO cells. 

PEA has been reported to be orally active in reducing edema formation and inflarmnatory hyperalgesia by dowmnodnlating mast cell activation (Mazzari et al., 1996). PEA has also been shown to act in synergy with AEA. Recently, Di Marzo and co-workers showed that PEA potently 

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