C M Timperley

Publications (8)20.68 Total impact

• Article: Competition radioligand binding assays for the investigation of bispyridinium compound affinities to the human muscarinic acetylcholine receptor subtype 5 (hM(5) ).

  K V Niessen, J E H Tattersall, C M Timperley, M Bird, C Green, H Thiermann, F Worek
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  ABSTRACT: Standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes lacks efficacy with some nerve agents. Promising in vitro and in vivo results were obtained with the bispyridinium compound SAD-128 which was partly attributed to its interaction with nicotinic acetylcholine receptors. Previous studies indicate that bispyridinium compounds interact with muscarinic acetylcholine receptors as well. The muscarinic M(5) receptor is not well investigated compared to other subtypes, but could be important in the search for new drugs for treating nerve agent poisoning. A set of bispyridinium compounds structurally related to SAD-128 were tested in competition binding experiments with recombinant human M(5) muscarinic acetylcholine receptors. Five of the six investigated bispyridinium compounds interacted with the orthosteric binding site, with affinities in the low micromolar range. These data indicate that interaction of bispyridinium compounds with muscarinic receptors may contribute to their therapeutic efficacy.
  Drug Testing and Analysis 02/2012; 4(3-4):292-7. · 2.54 Impact Factor
• Article: Restoration of soman-blocked neuromuscular transmission in human and rat muscle by the bispyridinium non-oxime MB327 in vitro.

  T Seeger, M Eichhorn, M Lindner, K V Niessen, J E H Tattersall, C M Timperley, M Bird, A C Green, H Thiermann, F Worek
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  ABSTRACT: The standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes is not sufficiently effective against all types of nerve agents. Alternative therapeutic strategies are required and bispyridinium non-oximes, acting as nicotinic antagonists, were identified as promising compounds. A previous study showed that the di(methanesulfonate) salt of the bispyridinium compound MB327 could restore soman-impaired neuromuscular function in vitro and improve survival of sarin, soman and tabun poisoned guinea pigs in vivo. Here, by using the indirect field stimulation technique, the ability of MB327 to counteract soman-impaired neuromuscular transmission was investigated in human intercostal muscle and rat diaphragm preparations. MB327 restored muscle force in a concentration-dependent manner in both species without reactivating soman-inhibited acetylcholinesterase. The therapeutic effect of MB327 could be washed out, indicating a direct effect at the nicotinic receptor level. Also the ability of MB327 to restore respiratory muscle function could be demonstrated for the first time in rat and human tissue. In combination with previous in vitro and in vivo findings MB327 may be considered a promising compound for the treatment of nerve agent poisoning and further studies are needed to identify optimized drug combinations, concentrations and dosing intervals to provide an effective therapy for OP poisoning.
  Toxicology 02/2012; 294(2-3):80-4. · 3.68 Impact Factor
• Article: Interaction of bispyridinium compounds with the orthosteric binding site of human α7 and Torpedo californica nicotinic acetylcholine receptors (nAChRs).

  K V Niessen, J E H Tattersall, C M Timperley, M Bird, C Green, T Seeger, H Thiermann, F Worek
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  ABSTRACT: Standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes lacks efficacy with different nerve agents. A direct pharmacologic intervention at the nicotinic acetylcholine receptor (nAChR) was proposed as an alternative therapeutic approach and promising in vitro and in vivo results were obtained with the bispyridinium compound SAD-128. In addition, a number of SAD-128 analogues improved neuromuscular transmission of soman-poisoned diaphragms in vitro. We investigated the interaction of six of these SAD-128 analogues with the orthosteric binding site of the human α7 nAChR and Torpedo californica nAChR with a high-throughput assay using radioactive ligands. The determined affinity constants indicate a weak interaction of three test compounds (K(i) in the micromolar range) with both receptors, but no interaction could be recorded with the other three test compounds. The six SAD-128 analogues showed a low intrinsic inhibitory potency with human acetylcholinesterase (IC₅₀ > 400 μM). In conclusion, the results of the present study do not indicate a correlation between the affinity to the orthosteric binding site and the functional improvement of neuromuscular transmission and it is assumed that other mechanisms contribute to the therapeutic effect of the tested compounds.
  Toxicology Letters 06/2011; 206(1):100-4. · 3.23 Impact Factor
• Article: Protection against nerve agent poisoning by a noncompetitive nicotinic antagonist.

  S R Turner, J E Chad, M Price, C M Timperley, M Bird, A C Green, J E H Tattersall
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  ABSTRACT: The acute toxicity of organophosphorus (OP) nerve agents arises from accumulation of acetylcholine (ACh) and overstimulation of ACh receptors. The mainstay of current pharmacotherapy is the competitive muscarinic antagonist, atropine. Nicotinic antagonists have not been used due to the difficulties of administering a dose of a competitive neuromuscular blocker sufficient to antagonise the effects of excessive ACh, but not so much that it paralyses the muscles. An alternative approach would be to use a noncompetitive antagonist whose effects would not be overcome by increasing ACh concentrations. This study demonstrates that the compound 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium), which blocks open nicotinic ion channels noncompetitively, is able to reverse the neuromuscular paralysis after nerve agent poisoning in vitro and to protect guinea pigs against poisoning by nerve agents when used as part of a therapeutic drug combination including a muscarinic antagonist. In contrast to the oxime HI-6, this compound was equally effective in protecting against poisoning by sarin or tabun. Further studies should identify more effective compounds with this action and optimise doses for protection against nerve agent poisoning in vivo.
  Toxicology Letters 05/2011; 206(1):105-11. · 3.23 Impact Factor
• Article: Fragmentations and reactions of the organophosphate insecticide Diazinon and its oxygen analog Diazoxon studied by electrospray ionization ion trap mass spectrometry.

  J D Barr, A J Bell, M Bird, J L Mundy, J Murrell, C M Timperley, P Watts, F Ferrante
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  ABSTRACT: The fragmentations and reactions of Diazinon and related compounds have been studied by electrospray ionization ion trap mass spectrometry. Several novel fragmentation and rearrangements have been observed, including an intramolecular thiono-thiolo rearrangement. The stability, in the gas-phase, of the protomers of 2-isopropyl-4-methyl-6-pyrimidinol has been demonstrated. The complexity of the gas phase ion processes observed suggest that, at present, caution should be exercised in using this approach for the analysis of environmental and other samples until our understanding of these processes increases considerably.
  Journal of the American Society for Mass Spectrometry 05/2005; 16(4):515-23. · 4.00 Impact Factor
• Article: Fragmentation and reactions of two isomeric O-alkyl S-(2-dialkylamino)ethyl methylphosphonothiolates studied by electrospray ionization/ion trap mass spectrometry.

  A J Bell, J Murrell, C M Timperley, P Watts
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  ABSTRACT: An initial investigation into the electrospray ionization ion trap mass spectrometry (ESI/ITMS) of simple organophosphorus compounds [1] demonstrated that detailed structural information could be obtained by sequential fragmentation of the ions using collision induced dissociation (CID). Several novel fragmentations/rearrangements were observed and it was apparent that the full potential of this approach could not be exploited until a more detailed understanding of the ion fragmentations was obtained. Such an understanding will only result from a detailed study of a wide range of compounds. The present paper describes the investigation of two isomeric organophosphates of particular relevance to chemical warfare convention (CWC) considerations.
  Journal of the American Society for Mass Spectrometry 09/2001; 12(8):902-10. · 4.00 Impact Factor
• Article: Fragmentations and reactions of some isotopically labelled dimethyl methyl phosphono and trimethyl phosphoro thiolates and thionates studied by electrospray ionisation ion trap mass spectrometry

  J.D. Barr, A.J. Bell, F. Ferrante, G. La Manna, J.L. Mundy, C.M. Timperley, M.J. Waters, P. Watts
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  ABSTRACT: In this paper, studies on electrospray ionisation ion trap mass spectrometry of organophosphates are extended to a series of dimethyl methylphosphono and trimethyl phosphoro thionates and thiolates and some deuterated isotopomers. Of particular, interest is the comparison of the collision-induced fragmentation of ions from these compounds with those of the non-sulphur containing analogues reported previously. The thiono and thiolo isomeric structures of the sulphur containing ions analogous to I and II (see below) have very similar energies and undergo a ready interconversion. In the case of the phosphono compounds, the electronic structure calculations show that the methyl migration implicit in thiono–thiolo interconversion occurs directly and although methyl migration from P to the phosphonyl O or phosphonothionyl S can occur, the transition state (TS) energies are somewhat higher and, in the case of the migration to O, too high to take part in any of the subsequent collision induced fragmentations. With one exception, the mechanisms proposed for some of these fragmentations are supported by electronic structure calculations at the DFT-B3LYP level.
  International Journal of Mass Spectrometry. 244(1):29-40.
• Article: Fragmentations and reactions of protonated O,O-dimethyl ethylphosphonate and some isotopomers produced by electrospray ionisation in an ion trap mass spectrometer

  A.J. Bell, F. Ferrante, S.E. Hall, V. Mikhailov, D. Mitchell, C.M. Timperley, P. Watts, N. Williams
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  ABSTRACT: The fragmentation behaviour of protonated O,O-dimethyl ethylphosphonate and its isotopomers deuterated in the α- and β-positions of the ethyl group and their fragment ions, particulary EtP(O)OMe+(IV), have been investigated both experimentally in an ion trap mass spectrometer and theoretically by electronic structure calculations at the B3LYP level. Of particular interest is the finding that the phosphonium ion IV eliminates ethene with hydrogen/deuterium loss from both the α-and β-positions. The initial step for both routes involves ethyl migration from P to O to form the ion MeOP+OEt which then loses ethene by two mechanisms, both of which lead to the same products. That a unitary branching ratio for α- and β-elimination is not observed indicates that although the final step of dissociation into product ion and ethene is energetically the most demanding, it is not rate limiting and the large entropy change associated with the dissociation allows earlier processes to determine the branching ratio. This demonstrates once again that free energy, not enthalpy (or energy), determines the course of gas phase ion processes.
  International Journal of Mass Spectrometry. 269:46-54.