TY - JOUR
T1 - Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists
AU - Manera, Clementina
AU - Saccomanni, Giuseppe
AU - Adinolfi, Barbara
AU - Benetti, Veronica
AU - Ligresti, Alessia
AU - Cascio, Maria Grazia
AU - Tuccinardi, Tiziano
AU - Lucchesi, Valentina
AU - Martinelli, Adriano
AU - Nieri, Paola
AU - Masini, Emanuela
AU - Di Marzo, Vincenzo
AU - Ferrarini, Pier Luigi
N1 - Keywords: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Humans; Jurkat Cells; Models, Molecular; Molecular Structure; Naphthyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
U2 - 10.1021/jm801563d
DO - 10.1021/jm801563d
M3 - Journal article
C2 - 19435366
SN - 0022-2623
VL - 52
SP - 3644
EP - 3651
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 12
ER -