Role for the Propofol Hydroxyl in Anesthetic Protein Target Molecular Recognition

Kellie A. Woll, Brian P. Weiser, Qiansheng Liang, Tao Meng, Andrew McKinstry-Wu, Benika Pinch, William P. Dailey, Wei Dong Gao, Manuel Covarrubias, Roderic G. Eckenhoff

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)927-935
Number of pages9
JournalACS Chemical Neuroscience
Volume6
Issue number6
DOIs
StatePublished - Jun 17 2015

Keywords

  • Anesthesia
  • GABAA receptor
  • hydrogen bonding
  • molecular recognition
  • propofol

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Woll, K. A., Weiser, B. P., Liang, Q., Meng, T., McKinstry-Wu, A., Pinch, B., Dailey, W. P., Gao, W. D., Covarrubias, M., & Eckenhoff, R. G. (2015). Role for the Propofol Hydroxyl in Anesthetic Protein Target Molecular Recognition. ACS Chemical Neuroscience, 6(6), 927-935. https://doi.org/10.1021/acschemneuro.5b00078