STRUCTURE-ACTIVITY ANALYSIS OF ANANDAMIDE ANALOGS - RELATIONSHIP TO ACANNABINOID PHARMACOPHORE

Anandamides are endogenous fatty acid ethanolamides that have been sho wn to bind to the cannabinoid receptor and possess cannabimimetic acti vity yet are structurally dissimilar from the classical cannabinoids f ound in Cannabis sativa. We have employed molecular dynamics studies o f a variety of anandamides to characterize their conformational mobili ty and determine whether there are pharmacophoric similarities with De lta(9)-THC. We have found that a looped conformation of these arachido nyl compounds is energetically favorable and that a structural correla tion between this low-energy conformation and the classical cannabinoi ds can be obtained with the superposition of (1) the oxygen of the car boxyamide with the pyran oxygen in Delta(9)THC, (2) the hydroxyl group of the ethanol with the phenolic hydroxyl group of Delta 9-THC, (3) t he five terminal carbons and the pentyl side chain of Delta 9-THC, and (4) the polyolefin loop overlaying with the cannabinoid tricyclic rin g. The shape similarity is extended to show that other fatty acid etha nolamides that possess varying degrees of unsaturation also vary in th eir conformational mobility, which affects their ability to overlay wi th Delta(9)-THC as described above. Within this series of compounds, t he most potent analog, the tetraene (arachidonyl) analog (i.e., ananda mide itself''), was determined to have restricted conformational mobil ity that favored an optimal pharmacophore overlay with Delta(9)-THC. E ight pharmacologically active anandamide analogs are shown to have sim ilar conformational mobility and pharmacophore alignments that are con formationally accessible. Furthermore, when these compounds are aligne d to Delta(9)THC according to the proposed pharmacophore overlay, thei r potencies are predicted by a quantitative model of cannabinoid struc ture-activity relationships based solely on classical and nonclassical cannabinoids with a reasonable degree of accuracy. The ability to inc orporate the pharmacological potency of these anandamides into the can nabinoid pharmacophore model is also shown to support the relevance of the proposed pharmacophore model.