Structural requirements for arachidonylethanolamide interaction with CB1 and CB2 cannabinoid receptors: pharmacology of the carbonyl and ethanolamide groups.
Analogs of arachidonylethanolamide (anandamide) were prepared to investigate the structural requirements for ligand binding to and activation of the CB1 and CB2 cannabinoid receptors. The importance of the presence and the placement of the carbonyl was examined with analogs lacking the carbonyl or with the carbonyl amide order reversed. The presence and location of the carbonyl is essential for high-affinity binding to both cannabinoid receptor subtypes, and for determination of signal transduction via G-proteins. Methyl groups were substituted on the 1'- and 2'-positions of arachidonylethanolamide and the significance of chirality was examined. Stereochemical differences in the ethanolamide group influence the affinity for both cannabinoid receptor subtypes and the signal transduction capabilities of the methanandamide derivatives.
Berglund
B A
BA
Department of Pharmacological and Physiological Science, St Louis University School of Medicine, MO 63104-1028, USA.
Boring
D L
DL
Wilken
G H
GH
Makriyannis
A
A
Howlett
A C
AC
Lin
S
S
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D063388:Endocannabinoids; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008024:Ligands; D014066:Palatine Tonsil / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013816:Thermodynamics
D001095:Arachidonic Acids; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D008024:Ligands; D010617:Phenanthridines; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C088155:methanandamide; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C032426:desacetylnantradol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; C078814:anandamide