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.

Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 4. Identification of New Potent and Selective Ligands for the Cannabinoid Type 2 Receptor with Diverse Substitution Patterns and Antihyperalgesic Effects in Mice

“…These findings, which are in agreement with the results recently reported for structurally related 1-substituted-1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, 25 deserve further attention as they represent a good starting point for the development of a novel class of CB2 ligand based on the 2-quinolone scaffold. Furthermore, we show here that at least four of the novel compounds, i.e.…”

What we know and do not know about the cannabinoid receptor 2 (CB2)

“…Structural changes in THC structure led to the synthesis of selective CB2 agonists, those most frequently used as pharmacological tools are HU-308 [88], a non-classical cannabinoid; JWH-133, a classical cannabinoid; and JWH-015 and AM124, aminoalkylindoles [81, 89]. New series of compounds have been recently described including diarylether sulfonylesters [90], pyrroles with neuro-protective properties [91], naphthyridin and quinolin derivatives [92, 93], which possess immune-modulatory properties [94, 95]. …”

Synthesis of 3,4-dihydro-1,8-naphthyridin-2(1H)-ones via microwave-activated inverse electron-demand Diels–Alder reactions

“…They show anti-allergic [6], anti-inflammatory [7], antibacterial [8] and gastric antisecretory activities [9]. Many other remarkable applications are reported in the literature [10–14], such as the selective inhibition of p38 mitogen-activated protein kinase [15] and the potent inhibition of protein kinase C isozymes [16]. Much attention has been devoted to the synthesis of 1,8-naphthyridin-2(1 H )-ones because of their acyl-CoA:cholesterol acyltransferase (ACAT) inhibitory activity [17] and their role as phosphodiesterase inhibitors [18–19].…”