Synthesis, conformational analysis and CB1 binding affinity of hairpin-like anandamide pseudopeptide mimetics. |
| |
Authors: | Maria Di Marzo Agostino Casapullo Giuseppe Bifulco Paola Cimino Alessia Ligresti Vincenzo Di Marzo Raffaele Riccio Luigi Gomez-Paloma |
| |
Affiliation: | Dipartimento di Scienze Farmaceutiche, Università di Salerno, 84084 Fisciano, Salerno, Italy. |
| |
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 microM in the same assay). The remaining pseudopeptides showed little binding to the CB(1) receptor (with K(i) values >or= 50 microM). 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 hairpin-like 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. |
| |
Keywords: | anandamide cannabinoids conformational analysis solid‐phase peptide synthesis |
|
|