Premium
Synthesis, conformational analysis and CB 1 binding affinity of hairpin‐like anandamide pseudopeptide mimetics
Author(s) -
Di Marzo Maria,
Casapullo Agostino,
Bifulco Giuseppe,
Cimino Paola,
Ligresti Alessia,
Marzo Vincenzo Di,
Riccio Raffaele,
GomezPaloma Luigi
Publication year - 2006
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.754
Subject(s) - anandamide , chemistry , affinities , cannabinoid receptor , binding affinities , stereochemistry , peptide , context (archaeology) , molecular dynamics , receptor , biochemistry , computational chemistry , biology , paleontology , agonist
Abstract 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.