Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists
| Autor: | Pier Luigi Ferrarini, Giuseppe Saccomanni, Adriano Martinelli, V. Benetti, Maria Grazia Cascio, Tiziano Tuccinardi, Alessia Ligresti, Barbara Adinolfi, Vincenzo Di Marzo, Clementina Manera, Valentina Lucchesi, Emanuela Masini, Paola Nieri |
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| Rok vydání: | 2009 |
| Předmět: |
Agonist
Models Molecular Cannabinoid receptor medicine.drug_class Stereochemistry Cell Survival medicine.medical_treatment Drug Evaluation Preclinical Carboxamide Antineoplastic Agents Crystallography X-Ray Jurkat cells Receptor Cannabinoid CB2 Jurkat Cells Structure-Activity Relationship Receptor Cannabinoid CB1 Cell Line Tumor Drug Discovery medicine Structure–activity relationship Humans Naphthyridines Receptor Cell Proliferation Dose-Response Relationship Drug Molecular Structure Chemistry Rational design Drug Design Molecular Medicine Cannabinoid |
| Zdroj: | Journal of medicinal chemistry. 52(12) |
| ISSN: | 1520-4804 |
| Popis: | The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13). Further studies revealed that compound 12, which presented benzyl and carboxy-4-methylcyclohexylamide substituents bound in the 1 and 3 positions, exerted a CB(2)-mediated inhibitory action on immunological human basophil activation. On the human T cell leukemia line Jurkat the same derivative induced a concentration-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists. |
| Databáze: | OpenAIRE |
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