On the basis of docking studies carried out using the recently published cannabinoid receptor models,(35) 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 [S-35]GTP gamma 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.
|Autori:||MANERA C; BENETTI V; CASTELLI MP; CAVALLINI C; LAZZAROTTI S; PIBIRI F; SACCOMANNI G; TUCCINARDI T; VANNACCI A; MARTINELLI A; FERRARINI PL|
|Titolo:||Design, Synthesis, and Biological Evaluation of New 1,8-Naphthyridin-4(1H)-one-3-carboxamide and Quinolin-4(1H)-one-3-carboxamide Derivatives as CB2 Selective Agonists|
|Anno del prodotto:||2006|
|Digital Object Identifier (DOI):||10.1021/jm0603466|
|Appare nelle tipologie:||1.1 Articolo in rivista|