(Aryloxy)alkylamines as Selective Human Dopamine D₄ Receptor Antagonists:  Potential Antipsychotic Agents

Abstract

The discovery of a series of novel (aryloxy)alkylamines with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. A number of compounds demonstrated subnanomolar K i values for binding to the D4 receptor, with several 100-fold selectivities toward the D2 and D3 receptors. Several compounds with combined D3/D4 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 [3H]thymidine in D4-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).

N-n-Propyl-Substituted 3-(Dimethylphenyl)piperidines Display Novel Discriminative Properties between Dopamine Receptor Subtypes: Synthesis and Receptor Binding Studies

“…In PPEs dimethyl-substituted on the phenyl ring, the meta position appears to be critical in order to provide both a high affinity for D 4 -DARs and a good selectivity between D 4 - and D 2 /D 3 - DARs. The importance of a methyl substituent on a phenyl ring for increasing the selectivity toward the D 4 -DARs versus D 2 /D 3 -DARs is in general agreement with the results of recent reports. , …”

Structure-Activity Relationship of Nerve-Highlighting Fluorophores

“…Nerve tissue sections were incubated with each crude fluorophore [24] at 1 mM, 100 µM, and 10 µM, where purity information obtained during initial characterization was used to adjust the amount of DMSO necessary to dissolve the product in the crude mixture at the same stock concentration ensuring that the same amount of novel fluorophore was incubated with each nerve section for ex vivo screening. Following incubation with the previously known nerve-specific fluorophores, homogenous fluorescence was seen throughout the nerve bundle, which was significantly higher than the background autofluorescence (Figure 2A).…”

Recent Progress in Medicinal Chemistry of D4 Agonists

“…This compound showed an intrinsic activity of 23% in regard to quinpirole. From the same screening also emerged (aryloxy)alkylamines 20, but only modest intrinsic activities were demonstrated (17 and 19%) with R= 3,4-diCH 3 , and R= 4-CH 3 respectively [72]. The 2-chloro compound was less selective towards D 2 R and the 3-chloro derivative more selective.…”