Synthesis and Evaluation of a Set of 4-Phenylpiperidines and 4-Phenylpiperazines as D2 Receptor Ligands and the Discovery of the Dopaminergic Stabilizer 4[3-(Methylsulfonyl)phenyl]-1-propylpiperidine (Huntexil, Pridopidine, ACR16)

Modification oldie partial dopamine type 2 receptor (D-2) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D-2 antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D, in vitro, without displaying properties essential for interaction with D-2 in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D-2 antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D-2 antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The agonist-like kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D, antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique dopaminergic stabilizer characteristics, differentiating 12b from D-2 antagonists and partial D-2 agonists.