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 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.
Tsai
R S
RS
Institut de Chimie Thérapeutique, Ecole de Pharmacie, Université de Lausanne, Switzerland.
Carrupt
P A
PA
Testa
B
B
Gaillard
P
P
el Tayar
N
N
Högberg
T
T
D065127:Dopamine D2 Receptor Antagonists; D006863:Hydrogen-Ion Concentration; D008968:Molecular Conformation; D011199:Potentiometry; D020891:Raclopride; D012457:Salicylamides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D065127:Dopamine D2 Receptor Antagonists; D012457:Salicylamides; D020891:Raclopride