Rational design, synthesis and anti-proliferative properties of new CB2 selective cannabinoid receptor ligands: An investigation of the 1,8-naphthyridin-2(1H)-one scaffold

• Published in: European journal of medicinal chemistry Vol. 52; pp. 284 - 294
• Main Authors: Manera, Clementina, Saccomanni, Giuseppe, Malfitano, Anna Maria, Bertini, Simone, Castelli, Francesca, Laezza, Chiara, Ligresti, Alessia, Lucchesi, Valentina, Tuccinardi, Tiziano, Rizzolio, Flavio, Bifulco, Maurizio, Di Marzo, Vincenzo, Giordano, Antonio, Macchia, Marco, Martinelli, Adriano
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.06.2012; Elsevier
• Subjects: Anti-proliferative; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cannabinoid; CB1 receptor; CB2 receptor; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Drug Design; Humans; Life Sciences & Biomedicine; Ligands; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - metabolism; Naphthyridines - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - metabolism; Science & Technology; Substrate Specificity; CB2 receptor; Anti-proliferative; Cannabinoid; CB1 receptor; LIVER-DISEASES; ENDOCANNABINOID SYSTEM; AMYOTROPHIC-LATERAL-SCLEROSIS; AGONISTS; MULTIPLE-SCLEROSIS; FUNCTIONAL EXPRESSION; MOUSE MODEL; BIOLOGICAL EVALUATION; 1,8-NAPHTHYRIDIN-4(1H)-ON-3-CARBOXAMIDE; DERIVATIVES
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2012.03.031

CB2 receptor ligands are becoming increasingly attractive drugs due to the potential role of this receptor in several physiopathological processes. Using our previously described series of 1,8-naphthyridin-2(1H)-on-3-carboxamides as a lead class, several nitrogen heterocyclic derivatives, characterized by different central cores, were synthesized and tested for their affinity toward the human CB1 and CB2 cannabinoid receptors. The obtained results suggest that the new series of quinolin-2(1H)-on-3-carboxamides, 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides and 1,2-dihydro-2-oxopyridine-3-carboxamides represent novel scaffolds very suitable for the development of promising CB2 ligands. Furthermore, the newly synthesized CB2 ligands inhibit proliferation of several cancer cell lines. In particular, it was demonstrated that in DU-145 cell line these ligands exert a CB2-mediated anti-proliferative action and decrease the CB2 receptor expression levels. [Display omitted] ► In this study we report the synthesis of new CB2R ligands. ► Some ligands possess high affinity and CB2/CB1 selectivity. ► The most active ligands are effective on different tumor cell lines.