TY - JOUR
T1 - Role for the Propofol Hydroxyl in Anesthetic Protein Target Molecular Recognition
AU - Woll, Kellie A.
AU - Weiser, Brian P.
AU - Liang, Qiansheng
AU - Meng, Tao
AU - McKinstry-Wu, Andrew
AU - Pinch, Benika
AU - Dailey, William P.
AU - Gao, Wei Dong
AU - Covarrubias, Manuel
AU - Eckenhoff, Roderic G.
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/6/17
Y1 - 2015/6/17
N2 - Propofol is a widely used intravenous general anesthetic. We synthesized 2-fluoro-1,3-diisopropylbenzene, a compound that we call fropofol, to directly assess the significance of the propofol 1-hydroxyl for pharmacologically relevant molecular recognition in vitro and for anesthetic efficacy in vivo. Compared to propofol, fropofol had a similar molecular volume and only a small increase in hydrophobicity. Isothermal titration calorimetry and competition assays revealed that fropofol had higher affinity for a protein site governed largely by van der Waals interactions. Within another protein model containing hydrogen bond interactions, propofol demonstrated higher affinity. In vivo, fropofol demonstrated no anesthetic efficacy, but at high concentrations produced excitatory activity in tadpoles and mice; fropofol also antagonized propofol-induced hypnosis. In a propofol protein target that contributes to hypnosis, α1β2γ2L GABAA receptors, fropofol demonstrated no significant effect alone or on propofol positive allosteric modulation of the ion channel, suggesting an additional requirement for the 1-hydroxyl within synaptic GABAA receptor site(s). However, fropofol caused similar adverse cardiovascular effects as propofol by a dose-dependent depression of myocardial contractility. Our results directly implicate the propofol 1-hydroxyl as contributing to molecular recognition within protein targets leading to hypnosis, but not necessarily within protein targets leading to side effects of the drug.
AB - Propofol is a widely used intravenous general anesthetic. We synthesized 2-fluoro-1,3-diisopropylbenzene, a compound that we call fropofol, to directly assess the significance of the propofol 1-hydroxyl for pharmacologically relevant molecular recognition in vitro and for anesthetic efficacy in vivo. Compared to propofol, fropofol had a similar molecular volume and only a small increase in hydrophobicity. Isothermal titration calorimetry and competition assays revealed that fropofol had higher affinity for a protein site governed largely by van der Waals interactions. Within another protein model containing hydrogen bond interactions, propofol demonstrated higher affinity. In vivo, fropofol demonstrated no anesthetic efficacy, but at high concentrations produced excitatory activity in tadpoles and mice; fropofol also antagonized propofol-induced hypnosis. In a propofol protein target that contributes to hypnosis, α1β2γ2L GABAA receptors, fropofol demonstrated no significant effect alone or on propofol positive allosteric modulation of the ion channel, suggesting an additional requirement for the 1-hydroxyl within synaptic GABAA receptor site(s). However, fropofol caused similar adverse cardiovascular effects as propofol by a dose-dependent depression of myocardial contractility. Our results directly implicate the propofol 1-hydroxyl as contributing to molecular recognition within protein targets leading to hypnosis, but not necessarily within protein targets leading to side effects of the drug.
KW - Anesthesia
KW - GABAA receptor
KW - hydrogen bonding
KW - molecular recognition
KW - propofol
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U2 - 10.1021/acschemneuro.5b00078
DO - 10.1021/acschemneuro.5b00078
M3 - Article
C2 - 25799399
AN - SCOPUS:84935018918
SN - 1948-7193
VL - 6
SP - 927
EP - 935
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 6
ER -