Rational Design, Synthesis, and Pharmacological Properties of New 1,8-Naphthyridin-2(1H)-on-3-Carboxamide Derivatives as Highly Selective Cannabinoid-2 Receptor Agonists

Dipartimento di Scienze Farmaceutiche, Universita di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 06/2009; 52(12):3644-51. DOI: 10.1021/jm801563d
Source: PubMed


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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    • "f 1 , 8 - naphthyridin - 4 ( 1H ) - on - 3 - carboxamide and 1 , 8 - naphthyridin - 2 ( 1H ) - on - 3 - carboxamide derivatives , that are highly selective CB2 recep - tor agonists . Some of these compounds showed CB2 receptor - mediated inhibitory action on immunological human basophil activation , decrease of cell viability on Jurkat cell line ( Manera et al . 2009 ) , in vivo antinociceptive effects ( Manera et al . 2007 ) and we recently demonstrated their potential application in multiple sclerosis ( Malfitano et al . 2013 ) . In this study , we investigated the immune - modulatory properties of these compounds on human PBMC expressing the CB2 receptor and , in particular , of a selected compou"
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    ABSTRACT: Considering the high selectivity at the cannabinoid CB2 receptor of recently designed 1,8-naphthyridine derivatives and the protective role of this receptor in neurological disorders, in this study we investigated the immune-modulatory and anti-inflammatory effects of these compounds as well as their potential properties of intestinal absorption and blood-brain barrier (BBB) permeability. We used peripheral blood mononuclear cells (PBMC) known to express the CB2 receptor. We observed that test compounds, CB13, CB82 and CB91 reduced PBMC proliferation. The anti-proliferative effect of CB13 and CB91 was partially mediated by the CB2 receptor. These compounds blocked the cells cycle and CB91 reduced T cell activation. CB82 and CB91 down-regulated the expression of phosphorylated proteins like NF-κB, ERK, Akt and the enzyme Cox-2, CB91 blocked the expression of the CB2 receptor and its inhibitory effect was CB2 receptor mediated. We also investigated CB91 properties of intestinal absorption and BBB permeability in order to suggest its potential efficacy on the infiltrating auto-reactive lymphocytes at the level of the central nervous system. For this purpose, CB91 was tested in drug-permeability assays on Caco-2 cells to evaluate its oral bioavailability and on MDCKII-hMDR1 cells to estimate its BBB permeability. The results indicated that this compound possesses medium level of intestinal absorption and BBB permeability. Our data suggest that CB91, modulating the immune response by CB2 receptor mediated mechanism and showing medium level of intestinal absorption and BBB permeability, might be developed as a potential orally delivered drug and might find potential application in pathologies like multiple sclerosis.
    Full-text · Article · Oct 2013 · Journal of Neuroimmune Pharmacology
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    • "Recently, novel CB2 receptor agonists, 1,8-naphthyridine, pyridine and quinoline derivatives [23], [24], [25], [26], [27] have been designed with high CB2 affinity and CB2 versus CB1 selectivity in agreement with molecular modeling studies [23]. Some of these compounds exhibited pharmacological properties like inhibitory action on immunological human basophil activation mediated by the CB2 receptor [23], [24]. Based on these findings, showing high CB2 selectivity and inhibitory effect on immune cell activation, in this study we investigated the potential immune-modulatory and anti-inflammatory effects of the described 1,8-naphthyridine pyridine and quinoline derivatives in activated peripheral blood mononuclear cells (PBMC) isolated from both MS patients and healthy donors. "
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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.
    Full-text · Article · May 2013 · PLoS ONE
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    ABSTRACT: Experimental evidence suggests that selective CB2 receptor modulators may provide access to antihyperalgesic agents devoid of psychotropic effects. Taking advantage of previous findings on structure-activity/selectivity relationships for a class of 4-quinolone-3-carboxamides, further structural modifications of the heterocyclic scaffold were explored, leading to the discovery of the 8-methoxy derivative 4a endowed with the highest affinity and selectivity ever reported for a CB2 ligand. The compound, evaluated in vivo in the formalin test, behaved as an inverse agonist by reducing at a dose of 6 mg/kg the second phase of the formalin-induced nocifensive response in mice.
    Full-text · Article · Jun 2011 · Journal of Medicinal Chemistry
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