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

Abstract

Conformations of analogs of acetylcholine and of related local anesthetics, in which either of the oxygen atoms had been replaced by other heteroatoms, were studied in solution by nuclear magnetic resonance.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...

NMR Conformational Study of Aminoalkylbenzamides, Aminoalkyl‐o‐anisamides, and Metoclopramide, a Dopamine Receptor Antagonist

“…These results contrast with those reported by Makriyannis et al [17] who for 6-HC1 in D,O observed an AA'BB'-system with J = 6.60 Hz, S = 5.70 Hz and ng = 0.74, n, = 0.26. Their data, however, were calculated from spectra recorded at 60 and 100 MHz and we believe that the A,B2-type spectrum was erroneously interpreted as an AA'BB -system.…”

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“…In the gauche conformation, the reduced distance of 3.3 Å between quaternary nitrogen and ether oxygen atoms increases intramolecular electrostatic stabilization, promoting that conformation. However, substituting sulfur or selenium for the ether oxygen atom results in absolute preference for the trans conformation (166, 231); steric crowding by the larger sulfur or selenium and changes in electron distribution likely offset electrostatic attraction to the quaternary nitrogen atom. Acetylthiocholine and acetylselenocholine are extremely weak agonists (229), suggesting the gauche conformation is essential for bioactivity.…”

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