Discovery of selective dopamine D4 receptor antagonists: 1-Aryloxy-3-(4-aryloxypiperidinyl)-2-propanols

High volume screening identified 3-(4-benzylpiperidinyl)-1-naphthoxy-2-propanol as a selective dopamine D4 receptor ligand. A systematic structure-activity study revealed that the benzyl group could be replaced with phenoxy and the naphthalene with phenyl to improve potency almost tenfold. The (R) enantiomer of this compound had a D4 affinity of 2 nM and was over 100-fold weaker at dopamine D2 and D3 receptors.