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.
Di Marzo
Maria
M
Dipartimento di Scienze Farmaceutiche, Università di Salerno, 84084 Fisciano, Salerno, Italy.
Casapullo
Agostino
A
Bifulco
Giuseppe
G
Cimino
Paola
P
Ligresti
Alessia
A
Di Marzo
Vincenzo
V
Riccio
Raffaele
R
Gomez-Paloma
Luigi
L
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