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Title: Computer simulations of local anesthetic mechanisms: Quantum chemical investigation of procaine

Abstract

A description at the atomic level of detail of the interaction between local anesthetics, lipid membranes and membrane proteins, is essential for understanding the mechanism of local anesthesia. The importance of performing computer simulations to decipher the mechanism of local anesthesia is discussed here in the context of the current status of understanding of the local anesthetics action. As a first step towards accurate simulations of the interaction between local anesthetics, proteins, lipid and water molecules, here we use quantum mechanical methods to assess the charge distribution and structural properties of procaine in the presence and in the absence of water molecules. The calculations indicate that, in the absence of hydrogen-bonding water molecules, protonated procaine strongly prefers a compact structure enabled by intramolecular hydrogen bonding. In the presence of water molecules the torsional energy pro?le of procaine is modified, and hydrogen bonding to water molecules is favored relative to intra-molecular hydrogen bonding.

Authors:
 [1];  [2];  [3];  [4]
  1. ORNL
  2. University of California, Irvine
  3. German Cancer Research Center, Heidelberg
  4. Institute of Atomic Physics, Bucharest Roumania
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
950810
DOE Contract Number:
DE-AC05-00OR22725
Resource Type:
Journal Article
Resource Relation:
Journal Name: Romanian Reports in Physics; Journal Volume: 59; Journal Issue: 2
Country of Publication:
United States
Language:
English
Subject:
08 HYDROGEN; ANESTHESIA; ANESTHETICS; BONDING; CHARGE DISTRIBUTION; COMPUTERIZED SIMULATION; HYDROGEN; LIPIDS; MEMBRANE PROTEINS; MEMBRANES; PROCAINE; PROTEINS; WATER

Citation Formats

Smith, Jeremy C, Bondar, A.N., Suhai, Sandor, and Frangopol, P.T. Computer simulations of local anesthetic mechanisms: Quantum chemical investigation of procaine. United States: N. p., 2007. Web.
Smith, Jeremy C, Bondar, A.N., Suhai, Sandor, & Frangopol, P.T. Computer simulations of local anesthetic mechanisms: Quantum chemical investigation of procaine. United States.
Smith, Jeremy C, Bondar, A.N., Suhai, Sandor, and Frangopol, P.T. Thu . "Computer simulations of local anesthetic mechanisms: Quantum chemical investigation of procaine". United States. doi:.
@article{osti_950810,
title = {Computer simulations of local anesthetic mechanisms: Quantum chemical investigation of procaine},
author = {Smith, Jeremy C and Bondar, A.N. and Suhai, Sandor and Frangopol, P.T.},
abstractNote = {A description at the atomic level of detail of the interaction between local anesthetics, lipid membranes and membrane proteins, is essential for understanding the mechanism of local anesthesia. The importance of performing computer simulations to decipher the mechanism of local anesthesia is discussed here in the context of the current status of understanding of the local anesthetics action. As a first step towards accurate simulations of the interaction between local anesthetics, proteins, lipid and water molecules, here we use quantum mechanical methods to assess the charge distribution and structural properties of procaine in the presence and in the absence of water molecules. The calculations indicate that, in the absence of hydrogen-bonding water molecules, protonated procaine strongly prefers a compact structure enabled by intramolecular hydrogen bonding. In the presence of water molecules the torsional energy pro?le of procaine is modified, and hydrogen bonding to water molecules is favored relative to intra-molecular hydrogen bonding.},
doi = {},
journal = {Romanian Reports in Physics},
number = 2,
volume = 59,
place = {United States},
year = {Thu Feb 01 00:00:00 EST 2007},
month = {Thu Feb 01 00:00:00 EST 2007}
}
  • Since it appears that D/sub 2/O is toxic in animals only when the concentration in the body fluids reaches high levels (> 20%), and since D/sub 2/O resembles the common solvent protium oxide more closely than any other, possible pharmaceutical applications of this solvent were explored. In studies in mice, D/ sub 2/O was used as a solvent for procaine and the effect on the stability and local anesthetic activity was noted. The ED/sub 50/ was determined by the method using corneal sensitivity, and comparison was made with procaine solutions in H/ sub 2/O. In H/sub 2/O the ED/sub 50/more » was 1.8% while in D/sub 2/O it was 1.0%. The LD/sub 50/was determined by intraperitoneal injection in mice. There appeared to be no significant difference in the toxicity of procaine in either solvent. Stability studies indicate that procaine is more stable in D/sub 2/O than H/sub 2/O at apparent pH values of 8.0, 8.5, and 9.0. Hence, the increased local anesthetic activity of procaine in D/sub 2/O may be accounted for by the fact that procaine free base is more stable in D/sub 2/O solutions, or that at the same apparent pH a D/sub 2/O solution of procaine will contain more free base than in the corresponding aqueous solution. (H.H.D.)« less
  • Nonequilibrium quantum chemical molecular dynamics (QM/MD) simulation of early stages in the nucleation process of carbon nanotubes from acetylene feedstock on an Fe38 cluster was performed based on the density-functional tight-binding (DFTB) potential. Representative chemical reactions were studied by complimentary static DFTB and density functional theory (DFT) calculations. Oligomerization and cross-linking reactions between carbon chains were found as the main reaction pathways similar to that suggested in previous experimental work. The calculations highlight the inhibiting effect of hydrogen for the condensation of carbon ring networks, and a propensity for hydrogen disproportionation, thus enriching the hydrogen content in already hydrogen-rich speciesmore » and abstracting hydrogen content in already hydrogen-deficient clusters. The ethynyl radical C2H was found as a reactive, yet continually regenerated species, facilitating hydrogen transfer reactions across the hydrocarbon clusters. The nonequilibrium QM/MD simulations show the prevalence of a pentagon-first nucleation mechanism where hydrogen may take the role of one arm of an sp2 carbon Y-junction. The results challenge the importance of the metal carbide formation for SWCNT cap nucleation in the VLS model and suggest possible alternative routes following hydrogen-abstraction acetylene addition (HACA)-like mechanisms commonly discussed in combustion synthesis.« less
  • The authors, after analysis of calculated and experimental data, conclude that the quenching of /sup 1/..delta.. /SUB g/ states due to the transfer of energy of vibrations of the solvent is not the only mechanism for deactivation. In the case of large aromatic molecules with small ionization potentials, there is the possibility of a second mechanism, which involves the direct enhancement of the spinorbit coupling of the /PHI//sub 0/ and /PHI//sub 1/ states owing to the presence of admixtures of charge-transfer states.
  • The radioprotective action of complexone III-procaine, p-aminobenzoic acid, and the ortho and meta isomers of this acid against Co/sup 6//sup 0/ gamma rays was studied and compared to the radioprotective effects of procaine, cysteamine, and aminoethyl isothiourea. The results showed that these compounds have a protective action inferior to that of procaine. In the three aminobenzoic acids the decreasing order of activity is ortho-para-meta. Procaine has a protective action at least equal to cysteamine and aminoethyl isothiourea. ( J.S.R.)