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

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 rac...

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Published in:Journal of medicinal chemistry 1993, Vol.36 (2), p.196-204
Main Authors: Tsai, Ruey Shiuan, Carrupt, Pierre-Alain, Testa, Bernard, Gaillard, Patrick, El Tayar, Nabil, Hoegberg, Thomas
Format: Article
Language:English
Subjects:
Biological and medical sciences
Dopamine D2 Receptor Antagonists
Hydrogen-Ion Concentration
Medical sciences
Molecular Conformation
Neuropharmacology
Pharmacology. Drug treatments
Potentiometry
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Raclopride
Salicylamides - chemical synthesis
Salicylamides - chemistry
Salicylamides - pharmacology
Solubility
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00054a002