title: Role for the propofol hydroxyl in anesthetic protein target molecular recognition.
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.
authors: Kellie A
authors: KA
authors: Woll
authors: Brian P
authors: BP
authors: Weiser
authors: §Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, JHN 417, Philadelphia, Pennsylvania 19107, United States.
authors: Qiansheng
authors: Q
authors: Liang
authors: ∥Department of Anesthesiology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012 P. R. China.|⊥Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, Maryland 21287, United States.
authors: Tao
authors: T
authors: Meng
authors: Andrew
authors: A
authors: McKinstry-Wu
authors: #Department of Chemistry, University of Pennsylvania School of Arts and Sciences, 231 S. 34th Street, Philadelphia, Pennsylvania 19104, United States.
authors: Benika
authors: B
authors: Pinch
authors: #Department of Chemistry, University of Pennsylvania School of Arts and Sciences, 231 S. 34th Street, Philadelphia, Pennsylvania 19104, United States.
authors: William P
authors: WP
authors: Dailey
authors: ⊥Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, Maryland 21287, United States.
authors: Wei Dong
authors: WD
authors: Gao
authors: §Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, JHN 417, Philadelphia, Pennsylvania 19107, United States.
authors: Manuel
authors: M
authors: Covarrubias
authors: Roderic G
authors: RG
authors: Eckenhoff
mesh_terms: D000494:Allosteric Regulation; D018686:Anesthetics, Intravenous / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006736:Horses; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007814:Larva; D008297:Male; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D015742:Propofol / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D018686:Anesthetics, Intravenous; D005464:Fluorobenzenes; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D015742:Propofol
keywords: Anesthesia; GABAA receptor; hydrogen bonding; molecular recognition; propofol