Novel Potent N-Methyl-d-aspartate (NMDA) Receptor Antagonists or 蟽1 Receptor Ligands Based on Properly Substituted 1,4-Dioxane Ring

详细信息    查看全文

• 作者：Alessandro Bonifazi ; Fabio Del Bello ; Valerio Mammoli ; Alessandro Piergentili ; Riccardo Petrelli ; Cristina Cimarelli ; Maura Pellei ; Dirk Schepmann ; Bernhard W眉nsch ; Elisabetta Barocelli ; Simona Bertoni ; Lisa Flammini ; Consuelo Amantini ; Massimo Nabissi ; Giorgio Santoni ; Giulio Vistoli ; Wilma Quaglia
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 12, 2015
• 年：2015
• 卷：58
• 期：21
• 页码：8601-8615
• 全文大小：630K
• ISSN：1520-4804

文摘

Two series of 1,4-dioxanes (4鈥?b>11 and 12鈥?b>19) were rationally designed and prepared to interact either with the phencyclidine (PCP) binding site of the N-methyl-d-aspartate (NMDA) receptor or with 蟽₁ receptors, respectively. The biological profiles of the novel compounds were assessed using radioligand binding assays, and the compounds with the highest affinities were investigated for their functional activity. The results were in line with the available pharmacophore models and highlighted that the 1,4-dioxane scaffold is compatible with potent antagonist activity at NMDA receptor or high affinity for 蟽₁ receptors. The primary amines 6b and 7 bearing a cyclohexyl and a phenyl ring or two phenyl rings in position 6, respectively, were the most potent noncompetitive antagonists at the NMDA receptor with IC₅₀ values similar to those of the dissociative anesthetic (S)-(+)-ketamine. The 5,5-diphenyl substitution associated with a benzylaminomethyl moiety in position 2, as in 18, favored the interaction with 蟽₁ receptors.