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‐pholometry 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 raciopride and other halogenated 6‐melhoxysalicylamides 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.