New insights on the molecular features and electrophysiological properties of dinotefuran, imidacloprid and acetamiprid neonicotinoid insecticides.

Structural features and hydrogen-bond interactions of dinotefuran (DIN), imidacoloprid (IMI) and acetamiprid (ACE) have been investigated experimentally through analyses of new crystal structures and observations in structural databases, as well as by Density Functional Theory quantum chemical calculations. Several conformations are observed experimentally in the solid state, highlighting the large flexibility of these compounds. This feature is confirmed by the theoretical calculations in the gas phase, the numerous and different energetic minima of the three neonicotinoids being located within a 10kJ/mol range. Comparisons of the observed and simulated data sheds light on the hydrogen-bond (HB) strength of the functional group at the tip of the electronegative fragment of each pharmacophore (NO(2) for DIN and IMI and CN for ACE). This effect originates in the 'push-pull' nature of these fragments and the related extensive electron delocalization. Molecular electrostatic potential calculations provide a ranking of the two fragments of the three neonicotinoid in terms of HB strength. Thus, the NO(2) group of DIN is the strongest HB acceptor of the electronegative fragment, closely followed by the cyano group of ACE. These two groups are significantly more potent than the NO(2) group of IMI. With respect to the other fragments of the three neonicotinoids, the nitrogen atom of the pyridine of IMI and ACE are stronger HB acceptors than the oxygen atom of the furanyl moiety of DIN. Finally, compared to electrophysiological studies obtained from cockroach synaptic and extrasynaptic receptors, DIN appears more effective than IMI and ACE because it strongly increases dose-dependently the ganglionic depolarisation and the currents amplitudes. These data suggest that DIN, IMI and ACE belong to two subgroups which act differently as agonists of insect nicotinic receptors.

[1]  Palmer Taylor,et al.  Atomic interactions of neonicotinoid agonists with AChBP: Molecular recognition of the distinctive electronegative pharmacophore , 2008, Proceedings of the National Academy of Sciences.

[2]  David B. Sattelle,et al.  Crystal structures of Lymnaea stagnalis AChBP in complex with neonicotinoid insecticides imidacloprid and clothianidin , 2008, Invertebrate Neuroscience.

[3]  W. J. Orville-Thomas.  Atoms in Molecules — a Quantum Theory , 1996 .

[4]  Palmer Taylor,et al.  Structure-guided drug design: conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes. , 2007, Biochemical pharmacology.

[5]  F. Allen,et al.  Hydrogen‐Bond Acceptor Properties of Nitro‐O Atoms: A Combined Crystallographic Database and Ab Initio Molecular Orbital Study , 1997 .

[6]  S. Thany.  Agonist actions of clothianidin on synaptic and extrasynaptic nicotinic acetylcholine receptors expressed on cockroach sixth abdominal ganglion. , 2009, Neurotoxicology.

[7]  Kathleen A. Durkin,et al.  The neonicotinoid electronegative pharmacophore plays the crucial role in the high affinity and selectivity for the Drosophila nicotinic receptor: an anomaly for the nicotinoid cation--pi interaction model. , 2003, Biochemistry.

[8]  F. Grolleau,et al.  Ca2+/calmodulin-dependent protein kinase regulates GABA-activated Cl- current in cockroach dorsal unpaired median neurons. , 2002, Journal of neurophysiology.

[9]  Zewen Liu,et al.  cis-Configuration: a new tactic/rationale for neonicotinoid molecular design. , 2011, Journal of agricultural and food chemistry.

[10]  S. Fomine,et al.  Are water–aromatic complexes always stabilized due to π–H interactions? LMP2 study , 2005 .

[11]  Peter W. Kenny,et al.  Hydrogen Bonding, Electrostatic Potential, and Molecular Design , 2009, J. Chem. Inf. Model..

[12]  Peter Politzer,et al.  Correlations between molecular electrostatic potentials and some experimentally-based indices of reactivity , 1992 .

[13]  J. Casida,et al.  Neonicotinoid insecticide toxicology: mechanisms of selective action. , 2005, Annual review of pharmacology and toxicology.

[14]  H. Hagelin,et al.  Family-independent relationships between computed molecular surface quantities and solute hydrogen bond acidity/basicity and solute-induced methanol O–H infrared frequency shifts , 1995 .

[15]  Shu-Kun Lin.  The Weak Hydrogen Bond: Applications to Structural Chemistry and Biology(International Union of Crystallography Monographs on Crystallography, 9). By Gautam R. Desiraju , 1999 .

[16]  D. Sattelle,et al.  Exploring the pharmacological properties of insect nicotinic acetylcholine receptors. , 2007, Trends in pharmacological sciences.

[17]  Donald G. Truhlar,et al.  Hybrid Meta Density Functional Theory Methods for Thermochemistry, Thermochemical Kinetics, and Noncovalent Interactions: The MPW1B95 and MPWB1K Models and Comparative Assessments for Hydrogen Bonding and van der Waals Interactions , 2004 .

[18]  Hirozumi Matsuno,et al.  Chloronicotinyl Insecticides. 8. Crystal and Molecular Structures of Imidacloprid and Analogous Compounds , 1997 .

[19]  P. Taylor,et al.  Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations , 2005, The EMBO journal.

[20]  T. Brinck.  Modified Interaction Properties Function for the Analysis and Prediction of Lewis Basicities , 1997 .

[21]  C. Macrae,et al.  Mercury CSD 2.0 – new features for the visualization and investigation of crystal structures , 2008 .

[22]  Richard F. W. Bader.  A quantum theory of molecular structure and its applications , 1991 .

[23]  P. Déglise,et al.  The insecticide imidacloprid is a partial agonist of the nicotinic receptor of honeybee Kenyon cells , 2002, Neuroscience Letters.

[24]  R. Nauen,et al.  Overview of the status and global strategy for neonicotinoids. , 2011, Journal of agricultural and food chemistry.

[25]  S. Thany,et al.  Effect of calcium on nicotine-induced current expressed by an atypical α-bungarotoxin-insensitive nAChR2 , 2008, Neuroscience Letters.

[26]  S. Buckingham,et al.  Imidacloprid actions on insect neuronal acetylcholine receptors , 1997, The Journal of experimental biology.

[27]  J. Galligan,et al.  Agonist actions of neonicotinoids on nicotinic acetylcholine receptors expressed by cockroach neurons. , 2007, Neurotoxicology.

[28]  Peter Pulay,et al.  Efficient elimination of basis set superposition errors by the local correlation method: Accurate ab initio studies of the water dimer , 1993 .

[29]  Kathleen A. Durkin,et al.  Neonicotinoid substituents forming a water bridge at the nicotinic acetylcholine receptor. , 2009, Journal of agricultural and food chemistry.

[30]  D. Sattelle,et al.  A simple technique for monitoring the synaptic actions of pharmacological agents. , 1973, The Journal of experimental biology.

[31]  Z. Liu,et al.  Pharmacological characterization of cis‐nitromethylene neonicotinoids in relation to imidacloprid binding sites in the brown planthopper, Nilaparvata lugens , 2010, Insect molecular biology.

[32]  S. Ranganathan,et al.  Correlations between the solvent hydrogen bond acceptor parameter β and the calculated molecular electrostatic potential , 1991 .

[33]  G. Wells.  Structural answers and persistent questions about how nicotinic receptors work. , 2008, Frontiers in bioscience : a journal and virtual library.

[34]  G. Oszlányi,et al.  Ab initio structure solution by charge flipping. , 2003, Acta crystallographica. Section A, Foundations of crystallography.

[35]  T. Steiner.  Donor and acceptor strengths in C–H···O hydrogen bonds quantified from crystallographic data of small solvent molecules , 1998 .

[36]  M. Berthelot,et al.  A theoretical evaluation of the pKHB and DeltaH[symbol: see text]HB hydrogen-bond scales of nitrogen bases. , 2008, Chemistry.

[37]  N. Ziao,et al.  Amino and cyano N atoms in competitive situations: which is the best hydrogen-bond acceptor? A crystallographic database investigation. , 2001, Acta crystallographica. Section B, Structural science.

[38]  N. Ziao,et al.  Amino nitrogen and carbonyl oxygen in competitive situations: which is the best hydrogen-bond acceptor site? , 2002 .

[39]  Frank Jensen,et al.  An Atomic Counterpoise Method for Estimating Inter- and Intramolecular Basis Set Superposition Errors. , 2010, Journal of chemical theory and computation.

[40]  R. Bader.  Atoms in molecules : a quantum theory , 1990 .

[41]  F. Allen.  The Cambridge Structural Database: a quarter of a million crystal structures and rising. , 2002, Acta crystallographica. Section B, Structural science.

[42]  M. Berthelot,et al.  Hydrogen-bond acceptor properties of nitriles: a combined crystallographic and ab initio theoretical investigation , 2000 .

[43]  T. Brinck.  The use of the electrostatic potential for analysis and prediction of intermolecular interactions , 1998 .

[44]  Peter Jeschke,et al.  Neonicotinoids-from zero to hero in insecticide chemistry. , 2008, Pest management science.

[45]  S. Buckingham,et al.  Neonicotinoids: insecticides acting on insect nicotinic acetylcholine receptors. , 2001, Trends in pharmacological sciences.

[46]  W. Delano.  The PyMOL Molecular Graphics System , 2002 .

[47]  (2E)-1-[(6-Chloropyridin-3-yl)methyl]-N-nitroimidazolidin-2-imine (imidachloprid) , 2004 .

[48]  Gervais Chapuis,et al.  SUPERFLIP– a computer program for the solution of crystal structures by charge flipping in arbitrary dimensions , 2007 .

[49]  Zewen Liu,et al.  Native subunit composition of two insect nicotinic receptor subtypes with differing affinities for the insecticide imidacloprid. , 2010, Insect biochemistry and molecular biology.

[50]  K. Harris,et al.  Weak interactions in crystal engineering—understanding the recognition properties of the nitro group , 2000 .

[51]  M. Berthelot,et al.  The exceptional hydrogen-bond properties of neutral and protonated lobeline. , 2007, The journal of physical chemistry. A.

[52]  Virginie B. Arnaud,et al.  Hydrogen-Bond Accepting Strength of Five-Membered N-Heterocycles: The Case of Substituted Phenylpyrrolines and Myosmines , 2009 .

[53]  J. Casida,et al.  Selective toxicity of neonicotinoids attributable to specificity of insect and mammalian nicotinic receptors. , 2003, Annual review of entomology.

[54]  S. Kagabu,et al.  Insecticidal and neuroblocking potencies of variants of the imidazolidine moiety of imidacloprid-related neonicotinoids and the relationship to partition coefficient and charge density on the pharmacophore. , 2007, Journal of agricultural and food chemistry.

[55]  Zewen Liu,et al.  Amino acids outside of the loops that define the agonist binding site are important for ligand binding to insect nicotinic acetylcholine receptors , 2008, Journal of neurochemistry.

[56]  S. Kagabu.  Discovery of imidacloprid and further developments from strategic molecular designs. , 2011, Journal of agricultural and food chemistry.

[57]  Zewen Liu,et al.  The mode of action of a nitroconjugated neonicotinoid and the effects of target site mutation Y151S on its potency. , 2011, Insect biochemistry and molecular biology.

[58]  J. Casida,et al.  Molecular recognition of neonicotinoid insecticides: the determinants of life or death. , 2009, Accounts of chemical research.

[59]  T. Sixma,et al.  Nicotine and Carbamylcholine Binding to Nicotinic Acetylcholine Receptors as Studied in AChBP Crystal Structures , 2004, Neuron.

[60]  Professor Dr. George A. Jeffrey,et al.  Hydrogen Bonding in Biological Structures , 1991, Springer Berlin Heidelberg.

[61]  Zewen Liu,et al.  Heteromeric co‐assembly of two insect nicotinic acetylcholine receptor α subunits: influence on sensitivity to neonicotinoid insecticides , 2009, Journal of neurochemistry.

[62]  Zhong Li,et al.  Actions between neonicotinoids and key residues of insect nAChR based on an ab initio quantum chemistry study: hydrogen bonding and cooperative pi-pi interaction. , 2007, Bioorganic & medicinal chemistry.

[63]  S. Thany.  Thiamethoxam, a poor agonist of nicotinic acetylcholine receptors expressed on isolated cell bodies, acts as a full agonist at cockroach cercal afferent/giant interneuron synapses , 2011, Neuropharmacology.

[64]  T. Mourik.  Assessment of Density Functionals for Intramolecular Dispersion-Rich Interactions. , 2008, Journal of chemical theory and computation.

[65]  Satoshi Miyagi,et al.  Identification of a high-affinity binding site for dinotefuran in the nerve cord of the American cockroach. , 2006, Pest management science.