title: Activation of retinal rod cGMP-gated channels: what makes for an effective 8-substituted derivative of cGMP?
abstract: Analogs of cGMP bearing diverse substituents at the C8 position of the guanine ring system have been shown to activate the cGMP-activated channel of retinal rods at concentrations lower than cGMP itself. In an effort to understand this behavior, we synthesized eight novel C8-substituted derivatives and tested their ability to activate channels in excised patches from salamander rod outer segments. We express the effectiveness of each analog as a ratio (in brackets) of the concentration required to open half of the channels in a patch to that required of 8-Br-cGMP, previously shown to be about 10 times more effective than cGMP. Five of the derivatives contained a thio substitution at C8: n-propylthio-cGMP [0.61], sulfoethylthio-cGMP [0.90], carboxyethylthio-cGMP [0.97], aminoethylthio-cGMP [2.8], and (trimethylamino)ethylthio-cGMP [8.5]. Three of the derivatives contained an amino substitution at C8: carboxyethylamino-cGMP [22], n-propylamino-cGMP [25], and aminoethylamino-cGMP [230]. The results indicate that thio-substitution at C8 produces more effective analogs than does amino-substitution, regardless of the chemical nature of the terminal functional group. Derivatives containing neutral and apolar tails opened channels at much lower concentrations than their positively-charged counterparts with the same C8 substituent. Analogs having negatively-charged tails were also more effective than those with positive charge but not quite as effective as those with neutral tails.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Physiology, University of Colorado School of Medicine, Denver 80262.
authors.forename: R L
authors.initials: RL
authors.lastname: Brown
authors.forename: R J
authors.initials: RJ
authors.lastname: Bert
authors.forename: F E
authors.initials: FE
authors.lastname: Evans
authors.forename: J W
authors.initials: JW
authors.lastname: Karpen
mesh_terms: D000557:Ambystoma; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000502:physiology*; D054815:Cyclic Nucleotide-Gated Cation Channels; D004305:Dose-Response Relationship, Drug; D007202:Indicators and Reagents; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007814:Larva; D015394:Molecular Structure; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects / Q000502:physiology*; D012374:Rod Cell Outer Segment / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D007202:Indicators and Reagents; D007473:Ion Channels; C016276:8-bromocyclic GMP; D006152:Cyclic GMP