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NMR Conformational Study of Aminoalkylbenzamides, Aminoalkyl‐ o ‐anisamides, and Metoclopramide, a Dopamine Receptor Antagonist
Author(s) -
Anker Lucien,
Van De Waterbeemd Han,
Testa Bernard,
Lauterweiin JÜRgen
Publication year - 1984
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19840670310
Subject(s) - chemistry , conformational isomerism , protonation , metoclopramide , benzamide , stereochemistry , intramolecular force , hydrogen bond , amide , side chain , dopamine receptor , nuclear magnetic resonance spectroscopy , molecule , receptor , organic chemistry , biochemistry , medicine , ion , surgery , vomiting , polymer
The conformational behaviour of metoclopramide, a neuroleptic benzamide, and model compounds was investigated byt 1 H‐NMR spectroscopy. An intramolecular amide‐methoxy H‐bond is shown to exist in CDCl 3 ‐solution, but not in D 2 O‐solution, independently of the length and protonation state of the basic side‐chain. This H‐bond creates a virtual cycle which may be a key feature for the binding of neuroleptic benzamides to the dopamine receptor. The conformational behaviour of the aminoethyl side‐chain is shown to be markedly condition‐dependent. For metoclopramide and its analogues in their protonated form, the gauche ‐ and trans ‐ rotamers have identical energies in D 2 O‐as well as in CDCl 3 ‐solutins. For the non‐protonated molecules, the trans ‐rotamer is favoured in D 2 O‐solutin, while the gauche ‐rotamer is favoured in CDCl 3 ‐solution (ΔG°≃|0.5|kcal/mol in both cases). The side‐chain conformation of neuroleptic benzamides is discussed in terms of receptor affinity.