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

✍ Scribed by Lucien Anker; Han Van De Waterbeemd; Bernard Testa; JÜRgen Lauterweiin

Book ID
102859447
Publisher
John Wiley and Sons
Year
1984
Tongue
German
Weight
605 KB
Volume
67
Category
Article
ISSN
0018-019X

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✦ Synopsis

The conformational behaviour of metoclopramide, a neuroleptic benzamide, and model compounds was investigated by 'H-NMR spectroscopy. An intramolecular amide-methoxy H-bond is shown to exist in CDC1,-solution, but not in D,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 nnetoclopramide and its analogues in their protonated form, the gauche-and trans-rotamers have identical energies in D,O-as well as in CDC1,-solutions. For the non-protonated molecules, the trans-rotamer is favoured in D,O-solution, while the gauche-rotamer is favoured in CDC1,-solution (AGO N 10.5lkcal/mol in both cases). The side-chain conformation of neuroleptic benzamides is discussed in terms of receptor affinity.

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