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Digital archive of theses discussed at the University of Pisa


Thesis etd-02172016-215225

Thesis type
Tesi di laurea magistrale LM5
Thesis title
Novel ligands directly enhancing the endocannabinoid system: design and synthesis of new N-(2-oxo-1,2-dihydropyridin-3-yl)cycloheptanecarboxamide derivatives
Course of study
relatore Prof.ssa Manera, Clementina
relatore Dott.ssa Gado, Francesca
  • 2-dihydropyridin-3-yl)cycloheptanecarboxamide deri
  • N-(2-oxo-1
  • Cannabinoid receptor
  • Endocannabinoid System
  • Cannabinoid receptor ligand
Graduation session start date
The endocannabinoid system is now known to be an ubiquitous neuromodulatory system with wide-ranging actions. It consists of endogenous cannabinoids (endocannabinoids), cannabinoid receptors and synthetic and degrading enzymes responsible for synthesis and degradation of endocannabinoids.
Endocannabinoids (EC) are lipid messengers derivatives of integral components of the cellular membranes: anandamide and 2-arachidonoylglycerol are the best characterized. Their levels are maintained mainly by two catabolic enzymes: the fatty acid amide hydrolase (FAAH) and the monoacylglyceride lipase (MAGL).
Cannabinoid receptors 1 and 2 (CB1 and CB2) belong to the superfamily of G-protein-coupled receptors. CB1 receptor is predominant in the central nervous system while CB2 receptor is located mainly in immune cells, such as macrophages, microglia, and B and T cells. As CB1 receptor mediates most, if not all, of the psychoactive effects of cannabinoids, CB2 receptor selective ligands are attractive as therapeutics because they would presumably lack this psychoactivity. Therefore, therapeutic strategies might include the use of cannabinoid receptor agonists and/or antagonists, but also the blockage of hydrolytic enzymes degrading ECs, the inhibition of EC transporters (EMT) and the inhibition of EC uptake. However, the current comprehension of the complexity of the endocannabinoid system seems to indicate a need of multitarget drugs, which exert their pro-cannabinoid activities by means of more than one mechanism of action. In fact, these molecules could offer the advantage of modulating the ECS in a safer and more therapeutically efficacious way.
In a previous research program aimed to obtain CB2 receptor selective ligands, a new series of 2-oxo-1,2-dihydropyridine-3-carboxamide derivatives which showed high CB2 receptor affinity and selectivity, were individuated.
Furthermore, the introduction of a substituent in position 5 of the heterocyclic nucleus showed an interesting effect on the activity on the CB2 receptor. Indeed, the nature of this substituent determined the control of the switch among the different types of pharmacological modulation: agonism, inverse agonism or antagonism on the receptor.
Subsequently the 5-substituted 2-oxo-1,2-dihydropyridine-3-carboxamide derivatives were modified through the insertion of a methyl group at the positions C4 or C6 These compounds were tested in order to evaluate the influence of a small substituent at the position 4 or 6 of the heterocyclic nucleus on the CBR affinity. The compounds of both series showed not only the best binding properties at CB2 receptors, but also the same behaviour towards these receptors. Furthermore, the 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives showed also to be inhibitors of AEA and 2-AG uptake with EC50 values in the nM range for some of them. Finally, some of these ligands showed to inhibit the fatty acid amide hydrolase (FAAH).
In the light of these good results, with the aim to deepen the structure activity relationship (SAR) of this series of compounds, during my thesis work, the N-(2-oxo-1,2-dihydropyridin-3-yl)cycloheptanecarboxamide derivatives were designed and synthesized as analogs of previous compounds in which the amide group in position C3 was substituted by the corresponding reverse amide.