(Aryloxy)alkylamines as selective human dopamine D-4 receptor antagonists: Potential antipsychotic agents

The discovery of a series of novel (aryloxy)alkyamines with selective affinity for the dopamine D-4 receptor is described, Target compounds were tested. for binding to cloned human dopamine D-2, D-3, and D-4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-l cells. A number of compounds demonstrated subnanomolar K-i values for binding to the D-4 receptor, with several 100-fold selectivities toward the D-2 and D-3 receptors. Several compounds with combined D-3/D-4 receptor binding selectivity were also identified, A limited structure-activity relationship study of this chemical series is discussed. In a mitogenesis functional assay, the effect of the test compounds on cellular uptake of [H-3]thymidine in D-4-transfected CHO 10001 cells was measured and compared to the response of the full dopamine agonist quinpirole. The activity of the compounds varied from full antagonist to weak partial agonist activity(intrinsic activity of 0-19% in comparison to quinpirole).