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Head Group Analogs of Arachidonylethanolamide, the Endogenous Cannabinoid Ligand

Head Group Analogs of Arachidonylethanolamide, the Endogenous Cannabinoid Ligand

  1. Nacumen
    Journal of medicinal chemistry, 25 October 1996, Vol.39(22), pp.4515-9

    Khanolkar, A D ; Abadji, V ; Lin, S ; Hill, W A ; Taha, G ; Abouzid, K ; Meng, Z ; Fan, P ; Makriyannis, A

    Several analogs of an endogenous cannabimimetic, arachidonylethanolamide (anandamide), were synthesized to study the structural requirements of the ethanolamide head group. CB1 receptor affinities of the analogs were evaluated by a standard receptor binding assay using tritiated CP-55,940 as the radioligand and compared to anandamide which was shown to have a Ki of 78 nM. Replacement of the amide carbonyl oxygen by a sulfur atom had a detrimental effect on the CB1 affinity. The thio analogs of both anandamide and (R)-methanandamide showed very weak affinity for CB1. The secondary nature of the amidic nitrogen was also shown to be important for affinity, indicating a possible hydrogen-bonding interaction between the amide NH and the receptor. Introduction of a phenolic moiety in the head group resulted in the loss of receptor affinity except when a methylene spacer was introduced between the amidic nitrogen and the phenol. A select group of analogs were also tested for their affinity for the CB2 receptor using a mouse spleen preparation and were found to possess low affinities fortheCB2sites. Notably,anandamideand(R)-methanandamidedemonstratedhighselectivity for the CB1 receptor. Overall, the data presented here show that structural requirements of the head group of anandamide are rather stringent.