Synthesis, conformational analysis and CB 1 binding affinity of hairpin‐like anandamide pseudopeptide mimetics

We have designed, synthesized and evaluated the CB 1 binding affinity of a number of new conformationally restricted lipopeptides ( 1 – 17 ). All of them present some of the AEA key structural elements incorporated in a hairpinlike peptide framework. Among them, compounds 1 – 3 and 8 showed CB 1 affinities in competitive binding assays with K i values in the micromolar range ( K i of AEA = 0.8 µ M in the same assay). The remaining pseudopeptides showed little binding to the CB 1 receptor (with K i values ≥ 50 µ M ). Conformational analysis on two representative compounds, performed by a combination of NMR studies, restrained molecular dynamics and QM calculations, allowed us to shed light on the structure‐activity relationships (SAR), pointing to a correlation between the predominance of the hairpinlike structural motif and the CB 1 binding affinity. In a more general context, the present study may also prove useful in gaining additional insight into the biological relevance of the various AEA conformations. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd.