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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, ?1?2?2L 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.

SUBMITTER: Woll KA

PROVIDER: S-EPMC4936777 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Role for the propofol hydroxyl in anesthetic protein target molecular recognition.

Woll Kellie A KA Weiser Brian P BP Liang Qiansheng Q Meng Tao T McKinstry-Wu Andrew A Pinch Benika B Dailey William P WP Gao Wei Dong WD Covarrubias Manuel M Eckenhoff Roderic G RG

ACS chemical neuroscience 20150330 6

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 ...[more]

PMID: 25799399

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Project description:BackgroundPhase lag entropy (PLE) is a novel anesthetic depth indicator that uses four-channel electroencephalography (EEG) to measure the temporal pattern diversity in the phase relationship of frequency signals in the brain. The purpose of the study was to evaluate the anesthetic depth monitoring using PLE and to evaluate the correlation between PLE and bispectral index (BIS) values during propofol anesthesia.MethodsIn thirty-five adult patients undergoing elective surgery, anesthesia was induced with propofol using target-controlled infusion (the Schneider model). We recorded the PLE value, raw EEG, BIS value, and hemodynamic data when the target effect-site concentration (Ce) of propofol reached 2, 3, 4, 5, and 6??g/ml before intubation and 6, 5, 4, 3, 2??g/ml after intubation and injection of muscle relaxant. We analyzed whether PLE and raw EEG data from the PLE monitor reflected the anesthetic depth as the Ce of propofol changed, and whether PLE values were comparable to BIS values.ResultsPLE values were inversely correlated to changes in propofol Ce (propofol Ce from 0 to 6.0??g/ml, r2?=?-?0.83; propofol Ce from 6.0 to 2.0??g/ml, r2?=?-?0.46). In the spectral analysis of EEG acquired from the PLE monitor, the persistence spectrogram revealed a wide distribution of power at loss of consciousness (LOC) and recovery of consciousness (ROC), with a narrow distribution during unconsciousness. The power spectrogram showed the typical pattern seen in propofol anesthesia with slow alpha frequency band oscillation. The PLE value demonstrated a strong correlation with the BIS value during the change in propofol Ce from 0 to 6.0??g/ml (r2?=?0.84). PLE and BIS values were similar at LOC (62.3 vs. 61.8) (P?>?0.05), but PLE values were smaller than BIS values at ROC (64.4 vs 75.7) (P?<?0.05).ConclusionsThe PLE value is a useful anesthetic depth indicator, similar to the BIS value, during propofol anesthesia. Spectral analysis of EEG acquired from the PLE monitor demonstrated the typical patterns seen in propofol anesthesia.Trial registrationThis clinical trial was retrospectively registered at ClinicalTrials.gov at October 2017 (NCT03299621).

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Role for the propofol hydroxyl in anesthetic protein target molecular recognition.

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Role for the propofol hydroxyl in anesthetic protein target molecular recognition.

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