NMR studies of interactions of new CB2 cannabinoid receptor ligands with cyclodextrins hosts. Correlation with micellar electrokinetic chromatography and reversed phase high performance liquid chromatography
- 274 Downloads
Three selective CB2 cannabinoid receptor ligands have recently been discovered to be promising anti-inflammatory agents but their low water solubility hinder their per os administration. The popularity of the cyclodextrins, from a pharmaceutical standpoint lies on their ability to interact with poorly water-soluble drugs and improve their solubility. Herein, three experimental approaches for calculating the stability constant of complexes between the selective CB2 ligands and either the β-CD or the HP-β-CD, were tested: nuclear magnetic resonance, micellar electrokinetic chromatography and high performance liquid chromatography in reversed phase. In NMR studies the calculated K values were relatively high and were between 1486 and 3571 M−1 with β-CD. With HP-β-CD they were between 1203 and 2650 M−1. Concerning the two others techniques the K values were found lower. In MECK studies with β-CD they were between 308 and 792 M−1 and with HP-β-CD between 124 and 764 M−1. Finally in RP-HPLC studies with β-CD, they were between 539 and 1144 M−1 and with HP-β-CD between 196 and 396 M−1. These calculated constants suggest that a complexation phenomenon occurs. A model for inclusion of one of the CB2 ligands in the β-CD was then proposed from molecular modeling studies.
KeywordsIBD 4-oxo-1 4-Dihydropyridine Solubility Formation constant Molecular modeling studies
This work was financially supported by a grant from the Nord-Pas-de-Calais Regional Council and University of Lille 2. The 500 MHz NMR facilities were funded by the Région Nord-Pas de Calais (France), the Ministère de la Jeunesse, de l’Education Nationale et de la Recherche (MJENR) and the Fonds Européens de Développement Régional (FEDER).
- 1.Massa, F., Marsicano, G., Hermann, H., Cannich, A., Monory, K., Cravatt, B.F., Ferri, G.L., Sibaev, A., Storr, M., Lutz, B.: The endogenous cannabinoid system protects against colonic inflammation. J. Clin. Invest. 113, 1202–1209 (2004)Google Scholar
- 4.Storr, M.A., Keenan, C.M., Emmerdinger, D., Zhang, H., Yüce, B., Sibaev, A., Massa, F., Buckley, N.E., Lutz, B., Göke, B., Brand, S., Patel, K.D., Sharkey, K.A.: Targeting endocannabinoid degradation protects against experimental colitis in mice: involve-ment of CB1 and CB2 receptors. J. Mol. Med. (Berl) 86, 925–936 (2008)CrossRefGoogle Scholar
- 5.Andrzejak, V., Muccioli, G.G., Body-Malapel, M., El Bakali, J., Djouina, M., Renault, N., Chavatte, P., Desreumaux, P., Lambert, D.M., Millet, R.: New FAAH inhibitors based on 3-carboxamido-5-aryl-isoxazole scaffold that protect against experimental colitis. Bioorg. Med. Chem. 19, 3777–3786 (2011)CrossRefGoogle Scholar
- 7.El Bakali, J., Muccioli, G.G., Renault, N., Pradal, D., Body-Malapel, M., Djouina, M., Hamtiaux, L., Andrzejak, V., Desreumaux, P., Chavatte, P., Lambert, D.M., Millet, R.: 4-Oxo-1,4-dihydropyridines as selective CB2 cannabinoid receptor ligands: structural insights into the design of a novel inverse agonist series. J. Med. Chem. 53, 7918–7931 (2010)CrossRefGoogle Scholar
- 8.El Bakali, J., Gilleron, P., Body-Malapel, M., Mansouri, R., Muccioli, G.G., Djouina, M., Barczyk, A., Klupsch, F., Andrzejak, V., Lipka, E., Furman, C., Lambert, D.M., Chavatte, P., Desreumaux, P., Millet, R.: 4-Oxo-1,4-dihydropyridines as selective CB2 cannabinoid receptor ligands part 2: discovery of new agonists endowed with protective effect against experimental colitis. J. Med. Chem. 55, 8948–8952 (2012)CrossRefGoogle Scholar
- 15.Job, P.: Recherches sur la formation de complexes minéraux en solution et leur stabilité. Ann. Chim. 9, 113–203 (1928)Google Scholar
- 21.Piel, G., Labres, L., Evrard, B., Van Hees, T., de Hassonville, S., Delattre, L.: A nuclear magnetic resonance study of the miconazole-β-cyclodextrin inclusion complex in an acidic medium: determination of the structure and stability constant. STP Pharm. Sci. 11, 235–238 (2001)Google Scholar
- 28.Lopez-Nicolas, J.M., Bunez-Delicado, E., Perez-Lopez, A.J., Carbonell Barrachina, A., Cuadra-Crespo, P.: Determination of stoichiometric coefficients and apparent formation constants for β-cyclodextrin complexes of trans-resveratrol using reversed-phase liquid chromatography. J. Chrom. A 1135, 158–165 (2006)CrossRefGoogle Scholar
- 31.Claude, B., Morin, Ph, Lafosse, M., Andre, P.: Evaluation of apparent formation constants of pentacyclic triterpene acids complexes with derivatized β- and γ-cyclodextrins by reversed phase liquid chromatography. J. Chrom. A 1049, 37–42 (2004)Google Scholar