Substituted cGMP analogs can act as selective agonists of the rod photoreceptor cGMP-gated cation channel

J Mol Neurosci. 1998 Feb;10(1):53-64. doi: 10.1007/BF02737085.


Cyclic nucleotide-gated (CNG) channels are expressed in many cell types in both the nervous system and nonexcitable tissues. In order to understand the roles of cGMP-gated channels, and to distinguish actions of cGMP mediated through CNG channels from those through cGMP-dependent protein kinase (G-kinase), several new cGMP analogs were tested for potency as CNG channel agonists. Using Xenopus oocytes expressing the rat rod cGMP-gated ion channel alpha-subunit, we showed that an analog containing a pCPT group at the 8-position, 8-pCPT-cGMP, was 80 times more potent than cGMP and 14 times more potent than 8-Br-cGMP. 8-pCPT-cGMP is the most potent CNG channel agonist so far described and also has the advantages of much better membrane permeability as well as much higher resistance to PDE-hydrolysis, as compared with 8-Br-cGMP. Modification of both 8-Br-cGMP and 8-pCPT-cGMP by introduction of a sulphur atom into the cyclic phosphate group gave smaller changes in agonist efficiency. Both Sp-8-Br-cGMPS and Sp-8-pCPT-cGMPS acted as agonists of CNG channels and are also G-kinase activators. In contrast, Rp-8-Br-cGMPS was a channel agonist, with an EC50 of 173.5 microM, but a G-kinase antagonist with a Ki of 4 microM. Finally, Rp-8-pCPT-cGMPS was a channel agonist and showed additional noncompetitive antagonist activity at higher concentrations. The results suggest that 8-pCPT-cGMPS is a highly potent photoreceptor CNG channel agonist with high membrane permeability and PDE-resistance and furthermore Rp-8-Br-cGMPS can be used to test whether the actions of cGMP are selectively mediated by CNG channels.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cyclic GMP / agonists*
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / metabolism
  • Cyclic GMP / pharmacology
  • Cyclic Nucleotide-Gated Cation Channels
  • Ion Channels / agonists*
  • Oocytes
  • Photoreceptor Cells / drug effects
  • Photoreceptor Cells / metabolism
  • Rats
  • Rod Cell Outer Segment / drug effects
  • Rod Cell Outer Segment / metabolism
  • Thionucleotides / pharmacology
  • Xenopus


  • 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
  • Cyclic Nucleotide-Gated Cation Channels
  • Ion Channels
  • Thionucleotides
  • 8-((4-chlorophenyl)thio)cyclic-3',5'-GMP
  • Cyclic GMP