Heterocyclic analogues of N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with functionalized linking chains as novel dopamine D3 receptor ligands: potential substance abuse therapeutic agents.

Abstract

Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effects induced by cocaine and other abused substances. Compound 6 [PG01037, (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-pyridine-2-ylbenzamide)] and related analogues are currently being evaluated in animal models of drug addiction. In these studies, a discrepancy between in vitro binding affinity, in vivo occupancy, and behavioral potency has been observed. The purpose of this study was to examine (1) modifications of the 2-pyridylphenyl moiety of 6 and (2) hydroxyl, acetyl, and cyclopropyl substitutions on the butylamide linking chain systematically coupled with 2-fluorenylamide or 2-pyridylphenylamide and 2-methoxy- or 2,3-dichloro-substituted phenylpiperazines to measure the impact on binding affinity, D2/D3 selectivity, lipophilicity, and function. In general, these modifications were well tolerated at the human dopamine D3 (hD3) receptor (Ki = 1-5 nM) as measured in competition binding assays. Several analogues showed >100-fold selectivity for dopamine D3 over D2 and D4 receptors. In addition, while all the derivatives with an olefinic linker were antagonists, in quinpirole-stimulated mitogenesis at hD3 receptors, several of the hydroxybutyl-linked analogues (16, 17, 21) showed partial agonist activity. Finally, several structural modifications reduced lipophilicities while retaining the desired binding profile.

• Authors: Peter Grundt, Katherine M Prevatt, Jianjing Cao, Michelle Taylor, Christina Z Floresca, Ji-Kyung Choi, Bruce G Jenkins, Robert R Luedtke, Amy Hauck Newman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 17 Pg. 4135-46 (Aug 23 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17672446 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Amides
• Benzamides
• Ligands
• N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide
• Piperazines
• Pyridines
• Receptors, Dopamine D3

Topics

• Amides (chemical synthesis, chemistry, pharmacology)
• Animals
• Benzamides (chemistry, pharmacokinetics)
• Binding, Competitive
• Brain (metabolism)
• Cell Line
• Humans
• Ligands
• Magnetic Resonance Imaging
• Mitosis (drug effects)
• Piperazines (chemical synthesis, chemistry, pharmacology)
• Pyridines (chemistry, pharmacokinetics)
• Radioligand Assay
• Rats
• Receptors, Dopamine D3 (agonists, antagonists & inhibitors)
• Stereoisomerism
• Structure-Activity Relationship
• Substance-Related Disorders (drug therapy)