New metabolically stable fatty acid amide ligands of cannabinoid receptors: Synthesis and receptor affinity studies

• Published in: Bioorganic & medicinal chemistry letters 2006, Vol.16 (1), p.138-141
• Main Authors: Urbani, Paolo, Cavallo, Paolo, Cascio, Maria Grazia, Buonerba, Mariafrancesca, De Martino, Giovanni, Di Marzo, Vincenzo, Saturnino, Carmela
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Amidohydrolases - chemistry; Anandamide; Arachidonic Acid - chemistry; Arachidonic Acids - chemistry; Biological and medical sciences; Cannabinoid; Cannabinoid Receptor Modulators - chemistry; Cannabinoids - chemistry; CB 1; CB 2; Cell Line; Chemistry, Pharmaceutical - methods; Chromatography; Drug Design; Endocannabinoids; Fatty Acids - chemistry; Humans; Inhibitory Concentration 50; Kinetics; Ligands; Medical sciences; Miscellaneous; Models, Chemical; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Polyunsaturated Alkamides; Protein Binding; Protein Structure, Tertiary; Receptor; Receptors, Cannabinoid - chemistry; Recombinant Proteins - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.09.023

Thirty-five novel stable fatty acid amide ligands selective for cannabinoid CB 1 receptors are reported, including some tertiary amides of arachidonic acid. 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.