Acetylcholine, predicted conformation

Figure 1. Predicted conformation of acetylcholine in muscarinic variant...

Calculations on oxotremorine (15), presumed to be a CNS muscarinic agent, revealed that this molecule, in its predicted conformation (Figure 5) mimicks this predicted muscarinic pharmacophore. The assumption is made that the electronic character of the triple bond is the receptor equivalent of the ether oxygen atom in acetylcholine as proposed by Bebbington (16). These calculations support his proposal and reveal how oxotremorine may meet the structural requirements of a muscarinic agent. 

The first application of all-valence electron MO theory to predict the conformation of a neurotransmitter was reported in 1967 on acetylcholine (8). Using EHT, the conformation of acetylcholine was predicted to assume an approximately gauche relationship between the nitrogen and ether oxygen atoms. This is in agreement with experimental evidence derived from aqueous solution NMR studies (9). Some flexibility was predicted for the CO-O bond so that the dimensions between the heteroatoms were predicted as shown in Figure 1. 

In recent years, the conformations of many of the more rigid ACh agonists have been determined by X-ray crystallography in order to predict (a) which of the many conformations, assumable by the loosely jointed molecule of acetylcholine, is the one active at a given receptor, and hence (b) the stereochemistry of the receptor itself Because of the known deformability of receptors (see Section 12.3), this approach is of only limited value but must be discussed. 

The purpose of this study has been to explore the possibility of theoretically predicting the conformation of a solute molecule in a dilute solution, by considering both intra-and inter-molecular interactions, where the latter term is meant to imply the solute-solvent interactions. Recently Beveridge et al. [1] have reported a study on the conformations of acetylcholine in solutions, in which intramolecular interactions were calculated by a molecular orbital method, and solvation energies were computed from the calculated solute properties and the experimental solvent parameters, following a method developed by Sinanoglu [2]. In the present study we consider two representative dipeptides, N-acetyl glycine N-methyl amide [3], and N-acetyl L-alanine N-methyl amide, whose conformations in inert solvents have been determined by NMR and infrared spectroscopic studies [4-8]. 

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