Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists.
ABSTRACT 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.
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ABSTRACT: The efficacy of cannabinoids in the treatment of multiple sclerosis is widely documented; however their use is limited by psychoactivity mainly ascribed to the activation of the cannabinoid receptor CB1. Emerging findings support as alternative strategy in the treatment of neurodegenerative disorders, the application of compounds targeting the CB2 receptor, since likely unrelated to these side effects. Recently, a novel class of compounds, 1,8-naphthyridine, pyridine and quinoline derivatives have been demonstrated to show high CB2 receptor selectivity and affinity versus the CB1 receptor. Considering that the CB2 receptor is mainly expressed in cell and organs of the immune system, in this study we assessed the potential immune-modulatory effects of these compounds in activated lymphocytes isolated from MS patients with respect to healthy controls. These compounds blocked cell proliferation through a mechanism partially ascribed to the CB2 receptor, down-regulated TNF-α production and did not induce cell death. They also down-regulated Akt, Erk and NF-kB phosphorylation. Despite comparable effects observed in patients and healthy controls, these compounds, in particular, 1,8-naphthyridine and quinoline derivatives inhibited cell activation markers in MS patient derived lymphocytes more efficiently than in healthy control derived cells. Indeed, 1,8-naphthyridin-2-one derivative reduced the levels of Cox-2 in lymphocytes from patients whereas no effect was observed in control cells. Our findings suggest potential application of these drugs in neuro-inflammation, supporting further investigations of the effects of compounds in the therapy of MS, particularly on the aspects regarding activation and inflammation.PLoS ONE 01/2013; 8(5):e62511. · 3.73 Impact Factor