Structure of Acetylcholine and Other Substrates of Cholinergic Systems

Canepa, F. G.; Pauling, Peter; Sørum, H.

doi:10.1038/210907a0

Cited by 140 publications

(44 citation statements)

References 15 publications

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“…The other feature of conformational interest is the twist of 91 ° about the O(1)-C(3) bond. The twist about the corresponding bond in acetylcholine is 79 ° in the crystal structure of the bromide (Canepa, Pauling & Sorum, 1966) and 167 ° in the chloride (Herdklotz & Sass, 1970). It appears that the conformation about this bond depends upon crystal packing forces.…”

Section: Discussionmentioning

confidence: 99%

The crystal structure of a homolog of acetylcholine: 3-acetoxypropyltrimethylammonium bromide

Craven¹,

Hite²

1973

Acta Crystallogr Sect B

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The crystal structure of 3-acetoxypropyltrimethylammonium bromide, [CH3COOCH2CH2CH2N(CH3)3]+Br -, is orthorhombic with space group P2~2~2~ and a= 10.62, b= 15.06, c=7.050 A. There are four formula units per cell. The molecular ion is nearly in the extended conformation except for the acetoxy group. There is a synclinal conformation about the C(2)-C(3) bond so that the C(I) and O(ether) atoms are separated by only 2.78 A.

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Section: Discussionmentioning

confidence: 99%

The crystal structure of a homolog of acetylcholine: 3-acetoxypropyltrimethylammonium bromide

Craven¹,

Hite²

1973

Acta Crystallogr Sect B

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“…It was found that replacement of the acyloxy oxygen by sulfur or selenium in crystals resulted in a drastic alteration of the conformation of either AcCh or of 2-dialkylaminoethyl benzoates. In either case, the gauche (sc) conformation of the -0-C-C-N-grouping (8,9) was altered to the fully extended trans(ap) conformation (10,11). On the other Abbreviation: AcCh, acetylcholine.…”

mentioning

confidence: 99%

Conformational Relationships Between Analogs of Acetylcholine and Those of Local Anesthetics in Solution

Makriyannis

Sullivan

Mautner

1972

Proc. Natl. Acad. Sci. U.S.A.

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Conformations of analogs of acetylcholine and of related local anesthetics, in which either of the oxygen atoms had been replaced by other heteroatoms, were studied in solution by nuclear magnetic resonance. Several correlations between structure and conformation could be made. Acetylcholine (AcCh) plays an essential role in transmission of nerve impulses, presumably by inducing a conformational change in the receptor biopolymer to which it is attached, thereby leading to an alteration of cation permeability. On the other hand, it has been postulated that local anesthetics block the conduction of nerve impulses by attachment to axonal AcCh receptors (2,3).In view of these considerations, it seemed of interest to investigate the following: (a) Effects of modifying the ester grouping on the conformations of analogs of AcCh and of local anesthetics in crystals and in solution, (b) factors involved in maintaining the conformations of such molecules, and (c) relationships between the conformations and biological actions of molecules, either triggering or blocking conduction of nerve impulses.One of the problems encountered when the structures of biologically active molecules are modified, is that even replacement of one atom by another may alter overall conformation and electron distribution throughout the molecule. Therefore, it is often difficult to decide whether a change in biological activity induced by modification of the structure of an active compound is due to an alteration of steric or of electronic factors.In an attempt to dissect steric from electronic factors, we synthesized a series of analogs of AcCh and local anesthetics in which either or both of the oxygens of the ester grouping were replaced by sulfur or by selenium (4-7). It was found that replacement of the acyloxy oxygen by sulfur or selenium in crystals resulted in a drastic alteration of the conformation of either AcCh or of 2-dialkylaminoethyl benzoates. In either case, the gauche (sc) conformation of the -0-C-C-N-grouping (8, 9) was altered to the fully extended trans(ap) conformation (10,11). On the other Abbreviation: AcCh, acetylcholine.hand, replacement of the carbonyl oxygen of AcCh with sulfur affected the gauche conformation of the -0-C-C-N-grouping to a very minor extent (12).It has been noted that in the case of AcCh (13) and its thiolester (14, 15) and selenolester (14) analogs, the conformation observed in the crystal also predominates in solution. The present study is concerned with the factors responsible for the conformations observed as well as with the relationships between analogs of AcCh and analogs of local anesthetics. RESULTSCompounds were synthesized according to methods given in references in Tables 1-3. 'H Resonance spectra were recorded at 60 MHz or 100MHz in Hitachi R-20-B or Varian HA-100 spectrometers. Compounds were examined in about 1 M solutions at 34°. Chemical shifts are recorded in ppm and measured from internal tetramethyl silane or sodium 3-trimethyl-silylpropionate-2,2,3,3-d4 references.XCH2CH2Y g...

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“…The different conformations of ACh can be derived from the rotation of the four internal torsional angles, 49 C 4 N 1 C 5 C 6 , N 1 C 5 C 6 O 7 , C 5 C 6 O 7 C 8 , and C 6 O 7 C 8 C 10 (Scheme 1). Two of these, C 4 N 1 C 5 C 6 and C 6 O 7 C 8 C 10 , are found to be trans in most of the previous experimental and theoretical studies. [11][12][13][30][31][32][38][39][40][41] The remaining torsions N 1 C 5 C 6 O 7 and C 5 C 6 O 7 C 8 are used to describe the conformational flexibility of ACh.…”

Section: Introductionmentioning

confidence: 94%

“…The conformational analysis of ACh has been the subject of many experimental [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] and theoretical investigations. The different conformations of ACh can be derived from the rotation of the four internal torsional angles, 49 C 4 N 1 C 5 C 6 , N 1 C 5 C 6 O 7 , C 5 C 6 O 7 C 8 , and C 6 O 7 C 8 C 10 (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Theoretical Investigations of Acetylcholine (ACh) and Acetylthiocholine (ATCh) Using ab Initio and Effective Fragment Potential Methods

et al. 2004

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Both the effective fragment potential method and fully ab initio HF and MP2 methods have been used to study solvation effects on the conformational potential energy surfaces of ACh and ATCh. Comparisons of hydrated geometries and relative energies show that EFP1 can generate results quite close to the much more time-consuming ab initio calculations. Hydrated structures of ACh and ATCh prefer bridged water structures. Very limited effects from the solvation have been observed in ACh and ATCh. In both the gas and aqueous solution, ACh prefers the gauche NCCO arrangement, whereas ATCh favors trans NCCS. Possible interpretations are discussed. Disciplines Chemistry CommentsReprinted (adapted) Both the effective fragment potential method and fully ab initio HF and MP2 methods have been used to study solvation effects on the conformational potential energy surfaces of ACh and ATCh. Comparisons of hydrated geometries and relative energies show that EFP1 can generate results quite close to the much more time-consuming ab initio calculations. Hydrated structures of ACh and ATCh prefer bridged water structures. Very limited effects from the solvation have been observed in ACh and ATCh. In both the gas and aqueous solution, ACh prefers the gauche NCCO arrangement, whereas ATCh favors trans NCCS. Possible interpretations are discussed.

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Structure of Acetylcholine and Other Substrates of Cholinergic Systems

Cited by 140 publications

References 15 publications

The crystal structure of a homolog of acetylcholine: 3-acetoxypropyltrimethylammonium bromide

The crystal structure of a homolog of acetylcholine: 3-acetoxypropyltrimethylammonium bromide

Conformational Relationships Between Analogs of Acetylcholine and Those of Local Anesthetics in Solution

Theoretical Investigations of Acetylcholine (ACh) and Acetylthiocholine (ATCh) Using ab Initio and Effective Fragment Potential Methods

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