Synthesis, conformational analysis and CB1 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 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.
Dipartimento di Scienze Farmaceutiche, Università di Salerno, 84084 Fisciano, Salerno, Italy.
Maria
M
Di Marzo
Agostino
A
Casapullo
Giuseppe
G
Bifulco
Paola
P
Cimino
Alessia
A
Ligresti
Vincenzo
V
Di Marzo
Raffaele
R
Riccio
Luigi
L
Gomez-Paloma
D000595:Amino Acid Sequence; D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D063385:Cannabinoid Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D063388:Endocannabinoids; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D053284:Polyunsaturated Alkamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; C078814:anandamide