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 T

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• 作者：Peter Grundt ; Katherine M. Prevatt ; Jianjing Cao ; Michelle Taylor ; Christina Z. Floresca ; Ji-Kyung Choi ; Bruce G. Jenkins ; Robert R. Luedtke ; Amy Hauck Newman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：August 23, 2007
• 年：2007
• 卷：50
• 期：17
• 页码：4135 - 4146
• 全文大小：426K
• 年卷期：v.50,no.17(August 23, 2007)
• ISSN：1520-4804

文摘

Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effectsinduced 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 beingevaluated in animal models of drug addiction. In these studies, a discrepancy between in vitro bindingaffinity, in vivo occupancy, and behavioral potency has been observed. The purpose of this study was toexamine (1) modifications of the 2-pyridylphenyl moiety of 6 and (2) hydroxyl, acetyl, and cyclopropylsubstitutions 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 bindingaffinity, D2/D3 selectivity, lipophilicity, and function. In general, these modifications were well tolerated atthe human dopamine D3 (hD3) receptor (K_i = 1-5 nM) as measured in competition binding assays. Severalanalogues showed >100-fold selectivity for dopamine D3 over D2 and D4 receptors. In addition, while allthe 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, severalstructural modifications reduced lipophilicities while retaining the desired binding profile.