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.
References
Dec 18, 1992·Science·W A DevaneR Mechoulam
Nov 1, 1991·Pharmacology, Biochemistry, and Behavior·B R MartinS J Ward
Jan 1, 1988·Proteins·P Dauber-OsguthorpeA T Hagler
Jan 1, 1995·Life Sciences·I B AdamsB R Martin
Jan 1, 1995·Life Sciences·G A CabralF Marciano-Cabral
Jan 19, 1996·Journal of Medicinal Chemistry·B F ThomasR K Razdan
Aug 1, 1996·British Journal of Pharmacology·E J IshacG Kunos
Oct 25, 1996·Journal of Medicinal Chemistry·A D KhanolkarA Makriyannis
Feb 7, 1997·The Journal of Biological Chemistry·T BisognoV Di Marzo
Feb 28, 1997·Journal of Medicinal Chemistry·T SheskinR Mechoulam
Jan 1, 1997·Advances in Experimental Medicine and Biology·V Di MarzoS Maurelli
Oct 23, 1998·Journal of Medicinal Chemistry·W TongA C Howlett
Nov 21, 1998·Journal of Medicinal Chemistry·J Barnett-NorrisP H Reggio
Jan 6, 1999·Journal of Medicinal Chemistry·S LinA Makriyannis
Aug 17, 1999·Biochemical and Biophysical Research Communications·D MelckV Di Marzo
Aug 26, 1999·Life Sciences·A D Khanolkar, A Makriyannis
Aug 31, 2002·Chemistry : a European Journal·Giampaolo BaroneGiuseppe Bifulco
Sep 15, 2004·Magnetic Resonance in Chemistry : MRC·Paola CiminoGiuseppe Bifulco
Citations
Sep 9, 2008·Medicinal Research Reviews·Lumír Ondrej Hanus
Dec 24, 2014·Life Sciences·F AtivieA Bilkei-Gorzo
Jul 1, 2019·Archives of Toxicology·Je-Oh LimJong-Choon Kim