Novel 4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New CB₂ Cannabinoid Receptors Agonists:  Synthesis, Pharmacological Properties and Molecular Modeling

Abstract

Recent data indicated that the CB(2) cannabinoid receptor constitutes an attractive drug target due to its potential functional role in several physiological and pathological processes. A set of 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives, characterized by the presence of some important structural requirements exhibited by other classes of cannabinoid ligands, such as an aliphatic or aromatic carboxamide group in position 3, and an alkyl or benzyl group in position 1, was synthesized and assayed to measure their respective affinity for both human CB(1) and CB(2) cannabinoid receptors. The results indicate that these 3-carboxamido-quinolones derivatives exhibited a CB(2) receptor selectivity, particularly derivatives 28-30, and 32R. Moreover, in the [(35)S]-GTPgammaS binding assay, all the compounds behaved as CB(2) receptor agonists. Molecular modeling studies showed that compound 30 interacts with the CB(2) receptor through a combination of hydrogen bond and aromatic/hydrophobic interactions. In conclusion, 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives constitute a new class of potent and selective CB(2) cannabinoid receptors agonists.

The methods of synthesis, modification, and biological activity of 4-quinolones (review)

“…The cyclization of the enamines 16 is realized by the action of heat in high-boiling solvents such as biphenyl [44], biphenyl ether [1, 26,32,34,36,37,41,42,[45][46][47], Dowtherm A [35,38,39,48,49], and mineral oil [1] or by using effective cyclization agents such as polyphosphoric acid or its esters [1, 2], the halogen derivatives of phosphorus [1], ZnCl 2 [1], conc. sulfuric acid in mixture with acetic anhydride [1], and Eaton's reagent (a mixture of phosphorus(V) oxide and methanesulfonic acid) [37,40].…”

Ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylates by a tandem addition‐elimination‐SNAr reaction

“…Earlier syntheses [4] of N-substituted 1,4-dihydro-4-oxo-3-quinolinecarboxylate esters have generally followed two strategies. In the first, conjugate addition of aniline to diethyl (ethoxymethylene)malonate to give a b-enamino diester was followed by thermal ring closure at 250 C and N-alkylation (overall yield ca.…”

“…50%). The disadvantage of this method is the high temperature used for the cyclization reaction, and the highly variable yields in the final alkylation [4,5]. For N-aryl cases, where alkylation by an S N 2 reaction is not possible, diphenylamine (the only case reported) was used to prepare the initial b-enamino diester [6].…”

Preparative enantiomeric separation of new selective CB2 receptor agonists by liquid chromatography on polysaccharide‐based chiral stationary phases: Determination of enantiomeric purity and assignment of absolute stereochemistry by X‐ray structure analysis

“…Functionality studies revealed the CB 2 cannabinoid receptor agonistic properties of our derivatives. 16,17 A lot of studies have shown that enantiomers of many drugs, including cannabinoid ligands, present different pharmacological profiles, independent metabolic pathways or various levels of toxicity. 18 Compounds 1-8 are characterized by a chiral center as shown in Figure 1.…”

“…The distomer (1)-1 exhibited an affinity of 784 nM which highlighted the stereoselective interaction to the CB 2 receptor. 16 Previous studies using liquid chromatography for the analytical resolution of 4-quinolone derivatives used derivatization procedures, or chiral mobile phase methods based on ligand exchange, or chiral stationary phases (CSPs) methods including crown ether, protein-based CSPs. 19 Further cellulose and amylose ester and carbamate derivatives coated onto a largepore silica gel backbone have proved to be extremely useful CSPs for chiral resolution and to the best of our knowledge, only a study by Radhakrishna et al 20 described the resolution of fluoroquinolone Moxifloxacin enantiomers on a cellulose carbamate derivative (Chiralcel OD-H) and on cellulose ester derivatives (Chiralcel OJ and OB).…”