Pharmacomodulations around the 4-Oxo-1,4-dihydroquinoline-3-carboxamides, a Class of Potent CB₂-Selective Cannabinoid Receptor Ligands:  Consequences in Receptor Affinity and Functionality

Abstract

CB2 receptor selective ligands are becoming increasingly attractive drugs due to the potential role of this receptor in several physiopathological processes. Thus, the development of our previously described series of 4-oxo-1,4-dihydroquinoline-3-carboxamides was pursued with the aim to further characterize the structure-affinity and structure-functionality relationships of these derivatives. The influence of the side chain was investigated by synthesizing compounds bearing various carboxamido and keto substituents. On the other hand, the role of the quinoline central scaffold was studied by synthesizing several 6-, 7-, or 8-chloro-4-oxo-1,4-dihydroquinolines, as well as 4-oxo-1,4-dihydronaphthyridine and 4-oxo-1,4-dihydrocinnoline derivatives. The effect of these modifications on the affinity and functionality at the CB2 receptor was studied and allowed for the characterization of new selective CB2 receptor ligands.

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].…”

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

“…17 Indeed CD spectra performed with the enantiomer (R) 21 revealed negative CD bands (Fig. 5a) and [a] 20 D value of 290.…”

“…17 Compounds 1-8 were obtained as racemates, and the enantiopure forms of 1-5 were also synthesized starting from the corresponding enantiopure amines. 17 Analytical chiral chromatography was performed on a silicabased amylose tris-3,5-dimethylphenylcarbamate (Chiralpak ADH; 250 Chromatographic data were collected and processed on a computer running with Millennium 2010 software. Mobile phase elution was made isocratically using n-hexane and a modifier (ethanol, 1-propanol, or 2-propanol) at various percentages.…”

“…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.…”

“…Refinement of (1) 31 x for the (R)-configuration using TWIN/BASF instructions gave the following value of 0.06 (17) in the final refinement.…”