Synthesis, cannabinoid receptor activity, and enzymatic stability of reversed amide derivatives of arachidonoyl ethanolamide.
Retroanandamide (2f) and its 10 analogues (1a-e, 2a-e) were synthesized and evaluated for the cannabinoid receptor activation by a [35S]GTPgammaS binding assay using rat cerebellar membranes, and Chinese hamster ovary cell membranes expressing human CB2 receptors. The primary goal of the study was to develop cannabinoid receptor agonists having improved enzymatic stability compared to endogenous N-arachidonoyl ethanolamide (AEA). Furthermore, by reversing the amide bond of AEA, the formation of arachidonic acid would be prevented. Finally, an effect of the carbonyl carbon position on the cannabinoid receptor activity was explored by synthesizing retroanandamide analogues having different chain lengths (1a-e, C19; 2a-f, C20). All the synthesized compounds, except 2c, behaved as partial agonists for the both cannabinoid receptors. In rat brain homogenate, the reversed amides possessed significantly higher stability against FAAH induced degradation than AEA. Therefore, the reversed amide analogues of AEA may serve as enzymatically stable structural basis for the drug design based on the endogenous cannabinoids.
Parkkari
Teija
T
Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. Teija.Parkkari@uku.fi
Savinainen
Juha R
JR
Raitio
Katri H
KH
Saario
Susanna M
SM
Matilainen
Laura
L
Sirviö
Tuomas
T
Laitinen
Jarmo T
JT
Nevalainen
Tapio
T
Niemi
Riku
R
Järvinen
Tomi
T
D000577:Amides / Q000737:chemistry*; D000581:Amidohydrolases / Q000187:drug effects*; D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D016466:CHO Cells; D063386:Cannabinoid Receptor Agonists; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004355:Drug Stability; D063388:Endocannabinoids; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D053284:Polyunsaturated Alkamides; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013462:Sulfur Radioisotopes; D000099252:Fatty Acid Amide Hydrolases
D000577:Amides; D000581:Amidohydrolases; D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D013462:Sulfur Radioisotopes; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide