New metabolically stable fatty acid amide ligands of cannabinoid receptors: Synthesis and receptor affinity studies.
We investigated the structure-activity relationships for the interactions of fatty acid amide analogs of the endocannabinoid anandamide with human recombinant cannabinoid receptors. Thirty-five novel fatty acid amides were synthesized using five different types of acyl chains and 11 different aromatic amine 'heads.' Although none of the new compounds was a more potent ligand than anandamide, we identified three amine groups capable of improving the metabolic stability of arachidonoylamides and their CB(1)/CB(2) selectivity ratio to over 20-fold, and several aromatic amines capable of improving the affinity of short chain or monosaturated fatty acids for cannabinoid CB(1) receptors. For the first time a tertiary amide of arachidonic acid was found to possess moderate affinity (K(i)=300 nM) for cannabinoid CB(1), but not CB(2), receptors.
Urbani
Paolo
P
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, via Campi Flegrei 34, Comprensorio Olivetti, Bldg. 70, 80078 Pozzuoli (NA), Italy.
Cavallo
Paolo
P
Cascio
Maria Grazia
MG
Buonerba
Mariafrancesca
M
De Martino
Giovanni
G
Di Marzo
Vincenzo
V
Saturnino
Carmela
C
D000577:Amides / Q000737:chemistry*; D000581:Amidohydrolases / Q000737:chemistry; D016718:Arachidonic Acid / Q000737:chemistry; D001095:Arachidonic Acids / Q000737:chemistry; D063385:Cannabinoid Receptor Modulators / Q000737:chemistry; D002186:Cannabinoids / Q000737:chemistry; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002845:Chromatography; D015195:Drug Design; D063388:Endocannabinoids; D005227:Fatty Acids / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D053284:Polyunsaturated Alkamides; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D043882:Receptors, Cannabinoid / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D000099252:Fatty Acid Amide Hydrolases
D000577:Amides; D000581:Amidohydrolases; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D005227:Fatty Acids; D008024:Ligands; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011994:Recombinant Proteins; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide