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@ARTICLE{Otte:856172,
      author       = {Otte, Maik and Schweinitz, Andrea and Bonus, Michele and
                      Enke, Uta and Schumann, Christina and Gohlke, Holger and
                      Benndorf, Klaus},
      title        = {{H}ydrophobic alkyl chains substituted to the 8-position of
                      cyclic nucleotides enhance activation of {CNG} and {HCN}
                      channels by an intricate enthalpy - entropy compensation},
      journal      = {Scientific reports},
      volume       = {8},
      number       = {1},
      issn         = {2045-2322},
      address      = {[London]},
      publisher    = {Macmillan Publishers Limited, part of Springer Nature},
      reportid     = {FZJ-2018-05799},
      pages        = {14960},
      year         = {2018},
      abstract     = {Cyclic nucleotide-gated (CNG) and
                      hyperpolarization-activated cyclic nucleotide-gated (HCN)
                      channels are tetrameric non-specific cation channels in the
                      plasma membrane that are activated by either cAMP or cGMP
                      binding to specific binding domains incorporated in each
                      subunit. Typical apparent affinities of these channels for
                      these cyclic nucleotides range from several hundred
                      nanomolar to tens of micromolar. Here we synthesized and
                      characterized novel cAMP and cGMP derivatives by
                      substituting either hydrophobic alkyl chains or
                      similar-sized more hydrophilic heteroalkyl chains to the
                      8-position of the purine ring with the aim to obtain full
                      agonists of higher potency. The compounds were tested in
                      homotetrameric CNGA2, heterotetrameric CNGA2:CNGA4:CNGB1b
                      and homotetrameric HCN2 channels. We show that nearly all
                      compounds are full agonists and that longer alkyl chains
                      systematically increase the apparent affinity, at the best
                      more than 30 times. The effects are stronger in CNG than
                      HCN2 channels which, however, are constitutively more
                      sensitive to cAMP. Kinetic analyses reveal that the off-rate
                      is significantly slowed by the hydrophobic alkyl chains.
                      Molecular dynamics simulations and free energy calculations
                      suggest that an intricate enthalpy - entropy compensation
                      underlies the higher apparent affinity of the derivatives
                      with the longer alkyl chains, which is shown to result from
                      a reduced loss of configurational entropy upon binding.},
      cin          = {JSC / ICS-6 / NIC},
      ddc          = {600},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)ICS-6-20110106 /
                      I:(DE-Juel1)NIC-20090406},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 511
                      - Computational Science and Mathematical Methods (POF3-511)
                      / 561 - Biological Key Regulators and Small Chemical
                      Compounds (POF3-561) / Forschergruppe Gohlke
                      $(hkf7_20170501)$ / Disinhibition and inhibition of HCN2
                      channel function by ligand binding to the cyclic nucleotide
                      bin $(hdd17_20170501)$},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-511 /
                      G:(DE-HGF)POF3-561 / $G:(DE-Juel1)hkf7_20170501$ /
                      $G:(DE-Juel1)hdd17_20170501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30297855},
      UT           = {WOS:000446577500037},
      doi          = {10.1038/s41598-018-33050-5},
      url          = {https://juser.fz-juelich.de/record/856172},
}