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Effects of solvation on the ionization and conformation of raclopride and other antidopaminergic 6-methoxysalicylamides: insight into the pharmacophore

Tsai, Ruey-Shiuan
Testa, Bernard
Gaillard, Patrick
el Tayar, Nabil
Hogberg, Thomas
Published in Journal of Medicinal Chemistry. 1993, vol. 36, no. 2, p. 196-204
Abstract Previous work has shown that raclopride in water at neutral pH exists in a zwitterionic form, suggesting a stereoelectronic structure largely different from that of other benzamides. In the present study, the acid-base behavior of other 6-methoxysalicylamides is shown to be comparable to that of raclopride. An extensive investigation by high-temperature molecular dynamics gave insight into the conformational behavior of neutral and zwitterionic raclopride in vacuum and in water. Partitioning of raclopride and a more rigid analogue with characterization (by first-derivative UV spectroscopy) of the predominant forms in the organic phase indicated that only neutral, internally H-bonded forms partition into the organic solvent. Thus, the predominant forms of 6-methoxysalicylamides will be very different in the aqueous and organic phases. In the latter phase, and hence presumably also in the receptor phase, the drugs exist with a neutral, internally H-bonded phenolic group and are therefore stereoelectronically similar to other substituted benzamides.
Keywords Hydrogen-Ion ConcentrationMolecular ConformationPotentiometryRacloprideReceptors, Dopamine D2/*antagonists & inhibitorsSalicylamides/*chemical synthesis/*chemistry/pharmacologySolubilityStereoisomerismStructure-Activity Relationship
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PMID: 8423592

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Deposited on : 2010-08-06

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