Design, Synthesis, and Biological Evaluation of New 1,8-Naphthyridin-4(1H)-on-3-carboxamide and Quinolin-4(1H)-on-3-carboxamide Derivatives as CB2 Selective Agonists

• Published in: Journal of medicinal chemistry 2006-10, Vol.49 (20), p.5947-5957
• Main Authors: Manera, Clementina, Benetti, Veronica, Castelli, M. Paola, Cavallini, Tiziana, Lazzarotti, Sara, Pibiri, Fabio, Saccomanni, Giuseppe, Tuccinardi, Tiziano, Vannacci, Alfredo, Martinelli, Adriano, Ferrarini, Pier Luigi
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Basophils - drug effects; Basophils - immunology; Biological and medical sciences; Brain - metabolism; Drug Design; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; In Vitro Techniques; Ligands; Male; Medical sciences; Mice; Mice, Inbred DBA; Miscellaneous; Models, Molecular; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Phosphoric Diester Hydrolases - biosynthesis; Pyrophosphatases - biosynthesis; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Radioligand Assay; Receptor, Cannabinoid, CB2 - agonists; Structure-Activity Relationship; Thermodynamics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0603466

On the basis of docking studies carried out using the recently published cannabinoid receptor models, new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the cannabinoid CB1 and CB2 receptors. Compound 10, which presented p-fluorobenzyl and carboxycycloheptylamide substituents bound in the 1 and 3 positions of the 1,8-naphthyiridine-4-one nucleus, showed a high CB2 affinity with a K i of 1.0 nM. The substitution of the naphthyridine-4-one nucleus with the quinoline-4-one system determined a general increase in CB2 affinity. In particular, the N-cyclohexyl-7-chloro-1-(2-morpholin-4-ylethyl)quinolin-4(1H)-on-3-carboxamide (40) possessed a remarkable affinity, with K i of 3.3 nM, which was also accompanied by a high selectivity for the CB2 receptor (K i(CB1)/K i(CB2) ratio greater than 303). Moreover, the [35S]GTPγ binding assay and functional studies on human basophils indicated that the 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives behaved as CB1 and CB2 receptor agonists.