Design, Synthesis, and Pharmacological Properties of New Heteroarylpyridine/Heteroarylpyrimidine Derivatives as CB2 Cannabinoid Receptor Partial Agonists

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• 作者：Mojgan Aghazadeh Tabrizi ; Pier Giovanni Baraldi ; Giulia Saponaro ; Allan R. Moorman ; Romeo Romagnoli ; Delia Preti ; Stefania Baraldi ; Carmen Corciulo ; Fabrizio Vincenzi ; Pier Andrea Borea ; Katia Varani
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：1098-1112
• 全文大小：490K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

Recent developments indicate that CB₂ receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB₂ receptor. Very recently, we have identified the oxazinoquinoline carboxamides as a novel class of CB₂ receptor full agonists. In this paper we describe the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives. Some of the reported compounds showed high affinity and potency at the CB₂ receptor while showing only modest affinity for the centrally expressed CB₁ cannabinoid receptor. Moreover, we found that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series show dose-dependent effects on the modulation of forskolin-induced cAMP production, revealing different behaviors as full agonists, partial agonists, and inverse agonists.