Analogues and homologues of N-palmitoylethanolamide, a putative endogenous CB(2) cannabinoid, as potential ligands for the cannabinoid receptors.
Lambert DM, DiPaolo FG, Sonveaux P, Kanyonyo M, Govaerts SJ, Hermans E, Bueb J, Delzenne NM, Tschirhart EJ
Unite de Chimie Pharmaceutique et de Radiopharmacie, Departement des Sciences pharmaceutiques, Universite catholique de Louvain, UCL 7340, Avenue Mounier 73, B-1200, Brussels, Belgium. lambert@ucl.cmfa.ac.be
The presence of CB(2) receptors was reported in the rat basophilic cell
line RBL-2H3 and N-palmitoylethanolamide was proposed as an endogenous,
potent agonist of this receptor. We synthesized a series of 10 N-palmitoylethanolamide
homologues and analogues, varying by the elongation of the fatty acid chain
from caproyl to stearoyl and by the nature of the amide substituent, respectively,
and evaluated the affinity of these compounds to cannabinoid receptors
in the rat spleen, RBL-2H3 cells and CHO-CB(1) and CHO-CB(2) receptor-transfected
cells. In rat spleen slices, CB(2) receptors were the predominant form
of the cannabinoid receptors. No binding of [(3)H]SR141716A was observed.
[(3)H]CP-55,940 binding was displaced by WIN 55,212-2 and anandamide. No
displacement of [(3)H]CP-55,940 or [(3)H]WIN 55,212-2 by palmitoylethanolamide
derivatives was observed in rat spleen slices. In RBL-2H3 cells, no binding
of [(3)H]CP-55,940 or [(3)H]WIN 55,212-2 could be observed and conversely,
no inhibitory activity of N-palmitoylethanolamide derivatives and analogues
was measurable. These compounds do not recognize the human CB(1) and CB(2)
receptors expressed in CHO cells. In conclusion, N-palmitoylethanolamide
was, in our preparations, a weak ligand while its synthesized homologues
or analogues were essentially inactive. Therefore, it seems unlikely that
N-palmitoylethanolamide is an endogenous agonist of the CB(2) receptors
but it may be a compound with potential therapeutic applications since
it may act via other mechanisms than cannabinoid CB(1)-CB(2) receptor interactions.
PMID: 10521710, UI: 99453276