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ACS Chem Neurosci
2015 Jun 17;66:927-35. doi: 10.1021/acschemneuro.5b00078.
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Role for the propofol hydroxyl in anesthetic protein target molecular recognition.
Woll KA, Weiser BP, Liang Q, Meng T, McKinstry-Wu A, Pinch B, Dailey WP, Gao WD, Covarrubias M, Eckenhoff RG.
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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.
Bhattacharya,
Binding of the general anesthetics propofol and halothane to human serum albumin. High resolution crystal structures.
2000, Pubmed
Bhattacharya,
Binding of the general anesthetics propofol and halothane to human serum albumin. High resolution crystal structures.
2000,
Pubmed Butts,
Identification of a fluorescent general anesthetic, 1-aminoanthracene.
2009,
Pubmed
,
Xenbase Cheng,
Computation of octanol-water partition coefficients by guiding an additive model with knowledge.
2007,
Pubmed Chiara,
Identification of nicotinic acetylcholine receptor amino acids photolabeled by the volatile anesthetic halothane.
2003,
Pubmed Ding,
Reversal of isoflurane-induced depression of myocardial contraction by nitroxyl via myofilament sensitization to Ca2+.
2011,
Pubmed Eckenhoff,
Steric hindrance is not required for n-alkanol cutoff in soluble proteins.
1999,
Pubmed Fang,
Anesthetic and convulsant properties of aromatic compounds and cycloalkanes: implications for mechanisms of narcosis.
1996,
Pubmed Franks,
Structural basis for the inhibition of firefly luciferase by a general anesthetic.
1998,
Pubmed Franks,
Molecular and cellular mechanisms of general anaesthesia.
1994,
Pubmed Fujinaka,
Effects of propofol on left ventricular mechanoenergetics in the excised cross-circulated canine heart.
2012,
Pubmed Gao,
Selective effects of oxygen free radicals on excitation-contraction coupling in ventricular muscle. Implications for the mechanism of stunned myocardium.
1996,
Pubmed Gredell,
Determination of diffusion and partition coefficients of propofol in rat brain tissue: implications for studies of drug action in vitro.
2004,
Pubmed Hall,
m-Azipropofol (AziPm) a photoactive analogue of the intravenous general anesthetic propofol.
2010,
Pubmed
,
Xenbase Hardegger,
Systematic investigation of halogen bonding in protein-ligand interactions.
2011,
Pubmed Hewapathirane,
In vivo imaging of seizure activity in a novel developmental seizure model.
2008,
Pubmed
,
Xenbase Hill-Venning,
Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor.
1997,
Pubmed
,
Xenbase Ishizawa,
G protein-coupled receptors as direct targets of inhaled anesthetics.
2002,
Pubmed Jayakar,
Identification of propofol binding sites in a nicotinic acetylcholine receptor with a photoreactive propofol analog.
2013,
Pubmed Jayakar,
Multiple propofol-binding sites in a γ-aminobutyric acid type A receptor (GABAAR) identified using a photoreactive propofol analog.
2014,
Pubmed Krasowski,
4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor.
2002,
Pubmed
,
Xenbase Krasowski,
General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility.
2001,
Pubmed
,
Xenbase Lam,
Modulatory and direct effects of propofol on recombinant GABAA receptors expressed in xenopus oocytes: influence of alpha- and gamma2-subunits.
1998,
Pubmed
,
Xenbase Leon,
Exploring microsolvation of the anesthetic propofol.
2012,
Pubmed León,
Mimicking anaesthetic-receptor interaction: a combined spectroscopic and computational study of propofol···phenol.
2012,
Pubmed León,
Formation of water polyhedrons in propofol-water clusters.
2013,
Pubmed Liu,
Truncated human serum albumin retains general anaesthetic binding activity.
2005,
Pubmed Liu,
Structural basis for high-affinity volatile anesthetic binding in a natural 4-helix bundle protein.
2005,
Pubmed Liu,
Comparative binding character of two general anaesthetics for sites on human serum albumin.
2004,
Pubmed McKinstry-Wu,
Discovery of a novel general anesthetic chemotype using high-throughput screening.
2015,
Pubmed
,
Xenbase Orser,
Propofol modulates activation and desensitization of GABAA receptors in cultured murine hippocampal neurons.
1994,
Pubmed Pavan,
Halogen bonding in fluorine: experimental charge density study on intermolecular F···F and F···S donor-acceptor contacts.
2013,
Pubmed Politzer,
An overview of halogen bonding.
2007,
Pubmed Rai,
Discovery of Novel General Anesthetics Using Apoferritin as a Surrogate System
2010,
Pubmed Royse,
Persistent depression of contractility and vasodilation with propofol but not with sevoflurane or desflurane in rabbits.
2008,
Pubmed Rudolph,
Molecular and neuronal substrates for general anaesthetics.
2004,
Pubmed Simons,
Distribution in female rats of an anaesthetic intravenous dose of 14C-propofol.
1991,
Pubmed Vedula,
A unitary anesthetic binding site at high resolution.
2009,
Pubmed Weiser,
In vivo activation of azipropofol prolongs anesthesia and reveals synaptic targets.
2013,
Pubmed
,
Xenbase Weiser,
An estimation of the global volume of surgery: a modelling strategy based on available data.
2008,
Pubmed Yip,
A propofol binding site on mammalian GABAA receptors identified by photolabeling.
2013,
Pubmed
