Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment

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• 作者：Vivek Kumar ; Alessandro Bonifazi ; Michael P. Ellenberger ; Thomas M. Keck ; Elie Pommier ; Rana Rais ; Barbara S. Slusher ; Eliot Gardner ; Zhi-Bing You ; Zheng-Xiong Xi ; Amy Hauck Newman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 25, 2016
• 年：2016
• 卷：59
• 期：16
• 页码：7634-7650
• 全文大小：727K
• 年卷期：0
• ISSN：1520-4804

文摘

The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D₃ receptor (D₃R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D₃R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D₃R crystal structure-guided 4-phenylpiperazines with exceptionally high D₃R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D₃R K_i = 6.84 nM, 1700-fold D₃R versus D₂R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D₃R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development.