IONIZATION BEHAVIOR AND IONIZATION-DEPENDENT CONFORMATION OF RACLOPRIDE, A DOPAMINE-D2 RECEPTOR ANTAGONIST

Raclopride, an antipsychotic 6-methoxysalicylamide ( = 2-hydroxy-6-methoxybenzamide) derivative, was shown by titrimetry and UV-photometry to exist in zwitterionic form at physiological pH. Calculations revealed that the neutral and zwitterionic forms differ considerably in their conformational behavior, the latter form being energetically favored by an intramolecular phenolate-ammonium ionic bond. These findings indicate that raclopride and other halogenated 6-methoxysalicylamides with a highly acidic phenolic group may not resemble other ortho-methoxybenzamides in their stereoelectronic structure and mode of binding to the dopamine D2 receptor.