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Structural requirements of Na+-dependent antidopaminergic agents: Tropapride, Piquindone, Zetidoline, and Metoclopramide Comparison with Na+-independent ligands

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Summary

Molecular graphic design coupled with PCILO and crystallographic results have been used to investigate the three-dimensional structure of Tropapride, Piquindone, Zetidoline, and Metoclopramide, four dopamine D-2 receptor antagonists showing Na+-dependent binding. Three putative pharmacophoric elements, a nitrogen lone pair, a phenyl ring and a carbonyl moiety, are similarly oriented in all the Na+-dependent drugs. Conversely, for Na+-independent analogs, the two latter pharmacophoric elements play a subordinate role, but two Π-electron regions are systematically localized on the other side of the molecule: the first is a phenyl group while the second is a carbonyl function as in butyrophenones, a cyano group as in R48455, or a phenyl ring as in diphenylbutylpiperidines or tricyclics. The presence of a benzyl ring on this side in Tropapride might explain its weak extrapyramidal effects.

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Authors and Affiliations

  1. Laboratoire de Chimie Moléculaire Structurale, Facultés Universitaires Notre-Dame de la Paix, Rue de Bruxelles 61, B-5000, Namur, Belgium

    Sonia Collin, Daniel P. Vercauteren, Didier Vanderveken, Guy Evrard & François Durant

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  1. Sonia Collin
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  2. Daniel P. Vercauteren
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  3. Didier Vanderveken
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  4. Guy Evrard
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  5. François Durant
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Collin, S., Vercauteren, D.P., Vanderveken, D. et al. Structural requirements of Na+-dependent antidopaminergic agents: Tropapride, Piquindone, Zetidoline, and Metoclopramide Comparison with Na+-independent ligands. J Computer-Aided Mol Des 3, 39–53 (1989). https://doi.org/10.1007/BF01590994

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  • DOI: https://doi.org/10.1007/BF01590994

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