Design, Synthesis, and Biological Evaluation of New 1,8-Naphthyridin-4(1H)-on-3-carboxamide and Quinolin-4(1H)-on-3-carboxamide Derivatives as CB2Selective Agonists
| Autor: | Sara Lazzarotti, V. Benetti, Alfredo Vannacci, Tiziano Tuccinardi, Fabio Pibiri, M. Paola Castelli, Giuseppe Saccomanni, and Adriano Martinelli, Pier Luigi Ferrarini, Clementina Manera, T. Cavallini |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Models Molecular Agonist Cannabinoid receptor Molecular model Stereochemistry medicine.drug_class Carboxamide In Vitro Techniques Ligands Chemical synthesis Receptor Cannabinoid CB2 Mice Radioligand Assay Structure-Activity Relationship Drug Discovery medicine Animals Humans Naphthyridines Pyrophosphatases Biological evaluation cannabinoid receptor agonist Phosphoric Diester Hydrolases Chemistry Brain Amides Basophils Design synthesis Guanosine 5'-O-(3-Thiotriphosphate) Mice Inbred DBA Docking (molecular) Drug Design Quinolines Thermodynamics Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 49:5947-5957 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0603466 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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