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.
SourceAvailable from: Mostafa Khouili[Show abstract] [Hide abstract]
ABSTRACT: Substituted 3,4-dihydro-1,8-naphthyridin-2(1H)-ones have been synthesized with the inverse electron-demand Diels–Alder reaction from 1,2,4-triazines bearing an acylamino group with a terminal alkyne side chain. Alkynes were first subjected to the Sonogashira cross-coupling reaction with aryl halides, the product of which then underwent an intramolecular inverse electrondemand Diels–Alder reaction to yield 5-aryl-3,4-dihydro-1,8-naphthyridin-2(1H)-ones by an efficient synthetic route.Beilstein Journal of Organic Chemistry 01/2014; 10:282-286. DOI:10.3762/bjoc.10.24 · 2.80 Impact Factor
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ABSTRACT: It has been well appreciated that the endocannabinoid system can regulate immune responses via the cannabinoid receptor 2 (CB2), which is primarily expressed by cells of the hematopoietic system. The endocannabinoid system is composed of receptors, ligands and enzymes controlling the synthesis and degradation of endocannabinoids. Along with endocannabinoids, both plant-derived and synthetic cannabinoids have been shown to bind to and signal through CB2 via G proteins leading to both inhibitory and stimulatory signals depending on the biological process. Because no cannabinoid ligand has been identified that only binds to CB2, the generation of mice deficient in CB2 has greatly expanded our knowledge of how CB2 contributes to immune cell development and function in health and disease. In regards to humans, genetic studies have associated CB2 with a variety of human diseases. Here, we review the endocannabinoid system with an emphasis on CB2 and its role in the immune system.Seminars in Immunology 05/2014; DOI:10.1016/j.smim.2014.04.002 · 6.12 Impact Factor
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ABSTRACT: The use of direct radiofluorination of aryliodonium salts represents a promising route to new PET tracers. This study tested the use of these precursors for obtaining candidate ligands of the cannabinoid type-2 receptor. 18F-labelling was performed using microfluidic technology, which allowed obtaining good incorporation yields. A closer inspection of the chemical composition of the reaction mixture evidenced the recurrent occurrence of chemical byproducts (H-adduct) due to a reductive side reaction of these substrates. The H-adduct formation seems to be unrelated to water presence, needed for obtaining a satisfactory incorporation, and may become an important feature for assessing the real-life accessibility of new radiotracers through the use of aryliodonium precursors.Journal of Radioanalytical and Nuclear Chemistry 08/2014; 303(1). DOI:10.1007/s10967-014-3407-4 · 1.42 Impact Factor