Structure−Activity Analysis of Anandamide Analogs:  Relationship to a Cannabinoid Pharmacophore

Abstract

Anandamides are endogenous fatty acid ethanolamides that have been shown to bind to the cannabinoid receptor and possess cannabimimetic activity yet are structurally dissimilar from the classical cannabinoids found in Cannabis sativa. We have employed molecular dynamics studies of a variety of anandamides to characterize their conformational mobility and determine whether there are pharmacophoric similarities with delta 9-THC. We have found that a looped conformation of these arachidonyl compounds is energetically favorable and that a structural correlation between this low-energy conformation and the classical cannabinoids can be obtained with the superposition of (1) the oxygen of the carboxyamide 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) the five terminal carbons and the pentyl side chain of delta9-THC, and (4) the polyolefin loop overlaying with the cannabinoid tricyclic ring. The shape similarity is extended to show that other fatty acid ethanolamides that possess varying degrees of unsaturation also vary in their conformational mobility, which affects their ability to overlay with delta 9-THC as described above. Within this series of compounds, the most potent analog, the tetraene (arachidonyl) analog (i.e., anandamide itself), was determined to have restricted conformational mobility that favored an optimal pharmacophore overlay with delta9-THC. Eight pharmacologically active anandamide analogs are shown to have similar conformational mobility and pharmacophore alignments that are conformationally accessible. Furthermore, when these compounds are aligned to delta 9-THC according to the proposed pharmacophore overlay, their potencies are predicted by a quantitative model of cannabinoid structure--activity relationships based solely on classical and nonclassical cannabinoids with a reasonable degree of accuracy. The ability to incorporate the pharmacological potency of these anandamides into the cannabinoid pharmacophore model is also shown to support the relevance of the proposed pharmacophore model.

Novel, potent THC/anandamide (hybrid) analogs

“…34,35 Our group has previously reported good AEA and Δ 9 -THC overlays (Thomas's model), which could predict by QSAR the potencies of various AEA analogs with a reasonable degree of accuracy. 36 We had found that a looped conformation of these AEA analogs is energetically favorable and that a structural correlation between this low energy conformation and the classical cannabinoids can be obtained with the superposition of (1) the oxygen of the carboxamide with the pyran oxygen in Δ 9 -THC, (2) the hydroxyl group of the ethanol with the phenolic hydroxyl group of Δ 9 -THC, (3) the five terminal carbons and the pentyl side chain of Δ 9 -THC, and (4) the polyolefin loop overlaying with the cannabinoid tricyclic ring. Our studies further showed that, when overlayed in this fashion, the potencies of AEA analogs are predictable by QSAR.…”

Conformational analysis of N‐arachidonylethanolamide (anandamide) using nuclear magnetic resonance and theoretical calculations

“…The structural correlation was checked considering the fitting in the following four molecular regions: (i) the carboxyamide oxygen of anandamide with the pyran oxygen of  9 -THC, (ii) the hydroxyl group of anandamide with the phenol hydroxyl group of  9 -THC, (iii) the polyolefin loop of anandamide with the cannabinoid tricyclic ring of  9 -THC and (iv) the terminal carbon of anandamide with the terminal carbon of  9 -THC. 21,22 An automated fitting procedure was used to minimize the root mean square deviation between atoms of anandamide and  9 -THC. This procedure was realized for all 22 conformational families obtained for anandamide.…”

Oxygenated Metabolites of Anandamide and 2-Arachidonoylglycerol: Conformational Analysis and Interaction with Cannabinoid Receptors, Membrane Transporter, and Fatty Acid Amide Hydrolase

“…Therefore, a structural comparison of active and inactive classical and synthetic cannabinoids has been used to derive pharmacophore models. [23][24][25] These models might also be used to predict and facilitate the design of novel compounds with greater potency or selectivity at the molecular target of interest. [23][24][25][26] A prerequisite for the building of such a pharmacophore model is to characterize an ensemble of active conformations of a molecule.…”