TY - JOUR
T1 - Highly selective dopamine D3 receptor (D3R) antagonists and partial agonists based on eticlopride and the D3R crystal structure
T2 - New leads for opioid dependence treatment
AU - Kumar, Vivek
AU - Bonifazi, Alessandro
AU - Ellenberger, Michael P.
AU - Keck, Thomas M.
AU - Pommier, Elie
AU - Rais, Rana
AU - Slusher, Barbara S.
AU - Gardner, Eliot
AU - You, Zhi Bing
AU - Xi, Zheng Xiong
AU - Newman, Amy Hauck
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/8/25
Y1 - 2016/8/25
N2 - 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 Ki = 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.
AB - 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 Ki = 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.
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U2 - 10.1021/acs.jmedchem.6b00860
DO - 10.1021/acs.jmedchem.6b00860
M3 - Article
C2 - 27508895
AN - SCOPUS:84983627400
SN - 0022-2623
VL - 59
SP - 7634
EP - 7650
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 16
ER -