Structure of acetylcholine tetraphenylborate

Datta, N.; Mondal, Pradip Kumar; Pauling, Peter

doi:10.1107/s0567740880004803

Cited by 16 publications

(13 citation statements)

References 3 publications

(2 reference statements)

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“…They located four of the five conformations we located, namely the gg, gt, tg, and tt conformations. Despite the flexibility of ACh expected from the gas-phase studies, solution NMR studies indicate that the gt form is preponderant in aqueous solution, and X-ray diffraction studies indicate that the gt and gg forms are preponderant in crystals of acetylcholine salts. − In fact for acetylcholine chloride, the cation retains the gt conformation in the crystal, in the semirigid clathrate structures of the small hydrates (up to seven water molecules), and in dilute solution .…”

Section: Results and Analysis Of Resultsmentioning

confidence: 99%

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Ionic Hydrogen Bonds in Bioenergetics. 4. Interaction Energies of Acetylcholine with Aromatic and Polar Molecules

Deakyne

Meot‐Ner

1999

J. Am. Chem. Soc.

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The binding energies of the quaternary ions (CH3)4N+ and acetylcholine (ACh) to neutral molecules have been measured by pulsed high-pressure mass spectrometry and calculated ab initio, to model interactions in the acetylcholine receptor channel. Binding energies to C6H6 and C6H5CH3 are similar to those to H2O (33−42 kJ/mol (8−10 kcal/mol)), but are weaker than those to polar organic ligands such as CH3CO2CH3 (50−63 kJ/mol (12−15 kcal/mol)) and to amides (up to 84 kJ/mol (20 kcal/mol)). These data suggest that aromatic residues that line the groove leading to the ACh receptor site may provide stabilization comparable to water, and therefore allow entry from the aqueous environment, yet do not bind ACh as strongly as polar protein groups, and therefore allow transit, without trapping, to the receptor site. Four of the five distinct ACh conformers located computationally are stabilized by internal C−H···O hydrogen bonds involving the quaternary ammonium group, which is supported by the thermochemistry of the protonated analogue, CH3CO2CH2CH2N(CH3)2H+, and by the measured bonding energy between models of the ACh end groups, (CH3)4N+ and CH3CO2CH3. Each conformer forms a number of stable complexes with water or benzene. Several possible roles for an ACh conformational change upon entry into the channel are discussed, including partial compensation for the loss of bulk solvation. An additional role for the aromatic environment is also suggested, namely lowering the energy barrier to the formation of the active all-trans ACh rotamer required at the receptor site.

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Section: Results and Analysis Of Resultsmentioning

confidence: 99%

“…Within a particular set of complexes the displacements are largest for the bridged structures. Nevertheless, the range of calculated dihedral angles is only 5° wider than the range observed experimentally. − ,, The data for all of the complexes have been tabulated and supplied as Supporting Information (Table S2).…”

Section: Results and Analysis Of Resultsmentioning

confidence: 99%

Ionic Hydrogen Bonds in Bioenergetics. 4. Interaction Energies of Acetylcholine with Aromatic and Polar Molecules

Deakyne

Meot‐Ner

1999

J. Am. Chem. Soc.

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“…For nicotine, cytisine and eserine, which are relatively rigid molecules, the X‐ray structures at highest resolution were considered (Cambridge Structural Database (CSD) entries DOXSIS ( Barlow et al , 1986 ), FITPIHO2 (Barlow & Johnson, 1989) and ESEIN10 (Pauling & Petcher, 1973), respectively). In contrast, for ACh and muscarine, which are more flexible molecules, all X‐ray structures were considered (CSD entries ACHOLC (Herdklotz & Sass, 1970), ACCHOBII (Svinning & Sourum, 1975), ACHTPB ( Datta et al , 1980 ) and GEBMEF ( Frydenvang et al , 1988 ) for ACh; HABNON (Frydenvang, 1990) and HABNUT (Frydenvang, 1990) for muscarine). The basic nitrogens were assumed to have a positively charged protonated form.…”

Section: Methodsmentioning

confidence: 99%

A structural model of agonist binding to the α3β4 neuronal nicotinic receptor

Costa

Nistri

Cavalli

et al. 2003

British J Pharmacology

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1 (a3) 2 (b4) 3 is the most abundant type of neuronal nicotinic ACh receptor (nAChR) mediating cholinergic actions on the autonomic nervous system. Studies to refine or devise drugs selectively acting on (a3) 2 (b4) 3 receptors would benefit from a detailed description of the hitherto unclear agonist-binding domain. 2 The present study reports a three-dimensional model for the ligand-binding domain (LBD) of this receptor either in its unoccupied or agonist-bound conformation. The receptor model was based on the structure of the acetylcholine-binding protein (AChBP), and was obtained using molecular modelling techniques. 3 ACh, nicotine and cytisine (full agonists), muscarine (a selective agonist of muscarinic ACh receptors) and the allosteric modulator eserine were docked into the binding pockets of the receptor model. Simulated agonist -receptor complexes were compared with the agonist-binding complex of the AChBP, as well as of the (a4) 2 (b2) 3 type of nAChR, which is the commonest in the brain. 4 Agonist docking identified discrete amino-acid residues of the b subunits important for pharmacological selectivity of nAChRs. The predicted affinity of muscarine for the nAChR was low, suggesting the present model to be suitable for effective discrimination of nicotinic agonist binding versus nonselective cholinergic binding. Furthermore, the current model outlined a potential binding site for the allosteric modulator eserine, the site of action of which has remained elusive. 5 The present LBD model of the receptor in its free state provides a novel structural framework to interpret experimental observations and a useful template for future investigations to develop (a3) 2 (b4) 3 -selective ligands.

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“…To understand the interactions of biologically interesting molecules, it is necessary to know the shape of the interaction sites as well as the conformations of the interacting molecules and, the conformational analysis of Ach has been subject of many experimental 6–25 and theoretical 26–46 investigations. Aspects of the Ach potential energy surface (PES) have been the subject of numerous experimental investigations including X‐Ray 6–8, 16–21, NMR 9, 11–14, 23, 25, electron diffraction 22, and Raman Spectroscopy 15, in addition, computational studies have employed ab initio 3, 31, 34, 35, 42–44, semi empirical and empirical methods 26–30, 38, 39 as well as molecular dynamics 36, 37, 45.…”

Section: Introductionmentioning

confidence: 99%

A DFT study of determination of the reactive sites of the acetylcholine and its agonists: In the gas phase and dielectric medium

Serdaroğlu

2011

Int J of Quantum Chemistry

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The reactive behavior of acetylcholine and its agonist molecules have been investigated using B3LYP hybrid density functional method at the 6-311þþG** basis set level, in the gas phase and aqueous phase. The calculations have been performed to obtain optimized geometries, relative reactivities, net atomic charges, HOMO, and LUMO energies. The solvent effect has been analyzed by using the continuum model (IPCM) and, the obtained results have shown that the all molecules have been stabilized more by solvent dielectric constant. For Ach and its analogues, it has been very well known that esteratic site and quaternary ammonium group which have reflected the difference in biological activity have been the two of the most important active site for interactions between molecule and its receptor. The structures of these analogues have provided an essential foundation for subsequent structureactivity analysis of ligand binding at acetylcholine receptors, neuronal uptake inhibitors and transporters. Molecular modeling predictions will be important initial steps toward the development of novel pharmaceuticals in the fight acetylcholine-related neurological disorders. This work is therefore expected to facilitate the design and development of new biologically active Ach analogues to treat Ach-related neurological disorders and, specially is used to qualitative understanding of the reactivity and related properties and, so on can be used to a preselection of new ligands which at the moment is taken essentially from empirical knowledge. V

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Structure of acetylcholine tetraphenylborate

Cited by 16 publications

References 3 publications

Ionic Hydrogen Bonds in Bioenergetics. 4. Interaction Energies of Acetylcholine with Aromatic and Polar Molecules

Ionic Hydrogen Bonds in Bioenergetics. 4. Interaction Energies of Acetylcholine with Aromatic and Polar Molecules

A structural model of agonist binding to the α3β4 neuronal nicotinic receptor

A DFT study of determination of the reactive sites of the acetylcholine and its agonists: In the gas phase and dielectric medium

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