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Cannabinoids are present in Indian hemp, Cannabis sativa L., and have been used since antiquity as medicinal agents(1). Interest in cannabinoid pharmacology has rapidly increased since the discovery of the endocannabinoid system (ECS), which includes cannabinoid receptors, the endocannabinoids (anandamide and 2-arachidonoylglycerol), metabolizing enzymes (fatty acid amide hydrolase and monoglyceride lipase), and aspecific cellular uptake system (the anandamide transporterprotein).
Cannabinoids exhibit a complex array of pharmacological effects that are generally considered to be mediated through at least two G-protein- coupled (GPCR) seven-transmembrane receptors. One of these receptors, designated CB1, is found principally in the central nervous system but it is also present in some peripheral organs. The CB2 receptor was originally identified from macrophages present in the spleen, and it is expressed primarily in the cells associated with the immune system, like spleen, thymus, and tonsils. The physiological and putative therapeutic potential of the CB2 receptor largely remains unexplored; however, recent data indicate that CB2 cannabinoid receptors participate in the control of peripheral pain, inflammation, osteoporosis, growth of malignant gliomas, tumors of immune origin, and immunological disorders such as multiple sclerosis. Furthermore, CB2 agents could be exploited for prevention of Alzheimer’s disease pathology, given of the presence of the CB2 receptor in the brain microglial cells,(2) and may be the basis for developing new drugs for the treatment of amyotrophic lateral sclerosis.(3) Because of the virtually exclusive peripheral expression of CB2, selective CB2 ligands should be devoid of the undesired central nervous system effects typical of (-)-trans-?9-tetrahydrocannabinol, the major psychoactive component of Cannabis sativa L.
In a previous work the binding results of a series of 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives(4) was reported. Furthermore, recently the three-dimensional models of the CB1 and CB2 receptors by means of a molecular modeling producer was constructed, and a series of CB2 ligands were, docked into both receptors, showing that the CB2 model was reliable and predictive.(5)
In this work, basing on the docking results, , I designed and synthesized new 7-methyl-1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, analogues derivatives in which the methyl group was removed or substituted with a chlorine atom, fluorine atom, metoxy group and dimethylamino group and new quinolin-4(1H)-on-3-carboxamide derivatives.
The studies of automated docking have showed that all the 1,8-naphthyridine derivatives tested could form an intramolecular H bond between the carbonylic oxygen and the amidic NH, creating a pseudocycle planar with the naphthyridine ring, and our studies suggested that this interaction was quite strong.(5)
To verify the hypothesis of the formation of a planar pseudocycle interaction inside the CB, I synthesized to tested some new compounds characterized by:
• the presence of a hydroxy group in position 4 of the naphthyridine nucleus, instead of the carbonyl oxygen atom, and by partial removal of the aromaticity of the cycle.
• closing of the O in position 4 with the amidic NH in a cycle to five atoms, to mime the pseudocycle planar of the energetic form more stable.
• shifting from position 3 to position 2 of the heterocyclic nucleus, of the carboxamide group.
Successful I synthesized new 1,8-naphthrydine characterized by the presence of a carbonilic group in position 2, to verify if this shift could be create a new interaction of binding site receptor. New 1,8-naphthrydine and quinoline derivatives characterized by the presence of a carbonilic group in positions 4 and 2, and finally to verify the importance of the presence of both aromatic rings in the central lipophilic bicyclic core, I have synthesized the pyridin compounds.

(1) Dewick, P. M. Medicinal Natural Products. A Biosynthetic Approach, 2nd ed.; John Wiley & Sons: New York, 2002; pp 86-89.
(2) Stella, N. Cannabinoid signaling in glial cells. Glia 2004, 48, 267-277.
(3) Kim, K.; Moore, D.H.; Markriyannis, A.; Abood, M.E.. Eur J Pharmacol. 2006, 542,100.
(4) Ferrarini, P. L.; Calderone, V.; Cavallini, T.; Manera, C.; Saccomanni, G.; Pani, L.; Ruiu, S.; Gessa, G. L .. Bioorg. Med. Chem. 2004, 12, 1921-1933.
(5) Tuccinardi, T.; Ferrarini, P. L.; Manera, C.; Ortore, G.; Saccomanni, G.; Martinelli, A. . J. Med. Chem. 2006, 49, 984-994.