Novel N7- and N1-Substituted cGMP Derivatives Are Potent Activators of Cyclic Nucleotide-Gated Channels

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• 作者：Timothy Strassmaier ; Jeffrey W. Karpen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：August 23, 2007
• 年：2007
• 卷：50
• 期：17
• 页码：4186 - 4194
• 全文大小：148K
• 年卷期：v.50,no.17(August 23, 2007)
• ISSN：1520-4804

文摘

Cyclic nucleotide-gated (CNG) channels, key players in olfactory and visual signal transduction, generateelectrical responses to odorant- and light-induced changes in cyclic nucleotide concentration. Previous worksuggests that substitutions are tolerated solely at the C8 position on the purine ring of cGMP. Our studieswith C8, 2'-OH, and 2-NH₂-modified cGMP derivatives support this assertion. To gain further insight intodeterminants important for CNG channel binding and activation, we targeted previously unexplored positions.Modifications at N7 of 8-SH-cGMP (6) are well tolerated by olfactory and retinal rod CNG channels.Toleration of a very large substituent, a 3400 molecular weight PEG, at either N7 or C8 argues for broadaccommodation at these positions in the binding site. Modification at N1 of cGMP reduces the apparentaffinity for the channel; however, when combined with 8-parachlorophenylthio derivatization, the resultingcGMP analogue is more potent than cGMP itself. These studies establish the N7 and N1 positions of cGMPas targets for modification in the design of novel CNG channel agonists.