3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter

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• 作者：Nicoletta Cini ; Elisa Danieli ; Gloria Menchi ; Andrea Trabocchi ; Anna Bottoncetti ; Silvia Raspanti ; Alberto Pupi and Antonio Guarna
• 关键词：DAT ; SERT ; Tropane ; Scaffold
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2006
• 出版时间：1 August 2006
• 年：2006
• 卷：14
• 期：15
• 页码：5110-5120
• 全文大小：250 K

文摘

CNS diseases such as Parkinson, schizophrenia, and attention deficit hyperactivity disorder (ADHD) are characterized by a significant alteration of dopamine transporter (DAT) density. Thus, the development of compounds that are able to selectively interact with DAT is of great interest. Herein we describe the design and synthesis of a new set of 3-aza-6,8-dioxabicyclo[3.2.1]octanes having a tropane-like structure with additional heteroatoms at positions 3 and 6. The compounds were evaluated for their in vitro receptor binding properties toward human dopamine (hDAT) and serotonin (hSERT) transporters using [³H]WIN35,428 and [³H]citalopram as specific radioligands, respectively. Biological assays revealed that some compounds having the N-3 atom substituted with aryl groups possess significant affinity and selectivity for monoamine transporters, and in particular, compound 5d displayed an IC₅₀ of 21 nM toward DAT, and a good selectivity toward SERT (IC₅₀ = 1042 nM). These results suggest that 3-aryl-3-aza-6,8-dioxabicyclo[3.2.1]octanes may represent a new class of DAT ligands.