1,2-Dihydro-2-oxopyridine-3-carboxamides: The C-5 substituent is responsible for functionality switch at CB2 cannabinoid receptor

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• 作者：Valentina Lucchesi^a ; Teija Parkkari^b ; ^c ; ^{Teija.Parkkari@uef.fi" class="auth_mail} ; Juha R. Savinainen^c ; Anna Maria Malfitano^d ; Marco Allarà ; ^f ; Simone Bertini^a ; Francesca Castelli^a ; Sara Del Carlo^a ; Chiara Laezza^e ; Alessia Ligresti^f ; Giuseppe Saccomanni^a ; Maurizio Bifulco^d ; Vincenzo Di Marzo^f ; Marco Macchia^a ; Clementina Manera^a ; ^{manera@farm.unipi.it" class="auth_mail}
• 关键词：Cannabinoid ; CB1 receptor ; CB2 receptor ; CB2 receptor neutral antagonist ; CB2 receptor inverse agonist
• 刊名：European Journal of Medicinal Chemistry
• 出版年：3 March, 2014
• 年：2014
• 卷：74
• 期：Complete
• 页码：524-532
• 全文大小：632 K

文摘

The relevance of CB2R-mediated therapeutic effects is well-known for the treatment of inflammatory and neuropathic pain and neurodegenerative disorders. In our search for new cannabinoid receptor modulators, we report the optimization of a series of 1,2-dihydro-2-oxopyridine-3-carboxamide derivatives as CB2R ligands. In particular, N-cycloheptyl-5-(4-methoxyphenyl)-1-(4-fluorobenzyl)-pyridin-2(1H)-on-3-carboxamide (17) showed high CB2R affinity (K_i聽=聽1.0聽nM), accompanied by interesting K_i(CB1R)/K_i(CB2R) selectivity ratio (SI聽=聽43.4). Compound 17 was also identified as a potent CB2R neutral antagonist/weak partial inverse agonist. Finally we found that the functionality activity of the series of 1,2-dihydro-2-oxopyridine is controlled by the presence of a substituent in position 5 of the heterocyclic nucleus. In fact when the hydrogen atom in position 5 of the unsubstituted compound 1 was replaced with a phenyl group (compound 18) the CB2R activity was shifted from agonism to inverse agonism whereas the introduction in the same position of p-methoxyphenyl group lead to compound 17 which showed a behavior as CB2R neutral antagonist/weak partial inverse agonist.