HEAD GROUP ANALOGS OF ARACHIDONYLETHANOLAMIDE, THE ENDOGENOUS CANNABINOID LIGAND

Several analogs of an endogenous cannabimimetic, arachidonylethanolami de (anandamide), were synthesized to study the structural requirements of the ethanolamide head receptor affinities of the analogs were eval uated by a standard receptor binding assay using tritiated CP-55,940 a s the radioligand and compared to anandamide which was shown to have a K-i of 78 nM. Replacement of the amide carbonyl oxygen by a sulfur at om had a detrimental effect on the CB1 affinity. The thio analogs of b oth anandamide and (R)-methanandamide showed very weak affinity for CB 1. The secondary nature of the amidic nitrogen was also shown to be im portant for affinity, indicating a possible hydrogen-bonding interacti on between the amide NH and the receptor. Introduction of a phenolic m oiety in the head group resulted in the loss of receptor affinity exce pt when a methylene spacer was introduced between the amidic nitrogen and the phenol. A select group of analogs were also tested for their a ffinity for the CB2 receptor using a mouse spleen preparation and were found to possess low affinities for the CB2 sites. Notably, anandamid e and (R)-methanandamide demonstrated high selectivity for the CB1 rec eptor. Overall, the data presented here show that structural requireme nts of the head group of anandamide are rather stringent.