Head group analogs of arachidonylethanolamide, the endogenous cannabinoid ligand
Khanolkar, A D; Abadji, V; Lin, S; Hill, W A; Taha, G; Abouzid, Khaled; Meng, Z; Fan, P; Makriyannis, A;
Abstract
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 for the CB2 sites. Notably, anandamide and (R)-methanandamide demonstrated high selectivity for the CB1 receptor. Overall, the data presented here show that structural requirements of the head group of anandamide are rather stringent.
Other data
Title | Head group analogs of arachidonylethanolamide, the endogenous cannabinoid ligand | Authors | Khanolkar, A D; Abadji, V; Lin, S; Hill, W A; Taha, G; Abouzid, Khaled ; Meng, Z; Fan, P; Makriyannis, A | Issue Date | 25-Oct-1996 | Journal | Journal of medicinal chemistry | Volume | 39 | Issue | 22 | Start page | 4515 | End page | 4519 | ISSN | 0022-2623 | DOI | 10.1021/jm960152y | PubMed ID | 8893848 | Scopus ID | 2-s2.0-0029960523 |
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