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.
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 Ki 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 Ki of 3.3 nM, which was also accompanied by a high selectivity for the CB2 receptor (Ki(CB1)/Ki(CB2) ratio greater than 303). Moreover, the [35S]GTPgamma 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.
Manera
Clementina
C
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. manera@farm.unipi.it
Benetti
Veronica
V
Castelli
M Paola
MP
Cavallini
Tiziana
T
Lazzarotti
Sara
S
Pibiri
Fabio
F
Saccomanni
Giuseppe
G
Tuccinardi
Tiziano
T
Vannacci
Alfredo
A
Martinelli
Adriano
A
Ferrarini
Pier Luigi
PL
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001491:Basophils / Q000187:drug effects / Q000276:immunology; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis; D011755:Pyrophosphatases / Q000096:biosynthesis; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000577:Amides; C427944:ENPP3 protein, human; D008024:Ligands; D009287:Naphthyridines; D011804:Quinolines; D043885:Receptor, Cannabinoid, CB2; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases