Novel N7- and N1-substituted cGMP derivatives are potent activators of cyclic nucleotide-gated channels.

Cyclic nucleotide-gated (CNG) channels, key players in olfactory and visual signal transduction, generate electrical responses to odorant- and light-induced changes in cyclic nucleotide concentration. Previous work suggests that substitutions are tolerated solely at the C8 position on the purine ring of cGMP. Our studies with C8, 2'-OH, and 2-NH2-modified cGMP derivatives support this assertion. To gain further insight into determinants 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 broad accommodation at these positions in the binding site. Modification at N1 of cGMP reduces the apparent affinity for the channel; however, when combined with 8-parachlorophenylthio derivatization, the resulting cGMP analogue is more potent than cGMP itself. These studies establish the N7 and N1 positions of cGMP as targets for modification in the design of novel CNG channel agonists.