title: Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment.
abstract: 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.
authors: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors: Vivek
authors: V
authors: Kumar
authors: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors: Alessandro
authors: A
authors: Bonifazi
authors: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors: Michael P
authors: MP
authors: Ellenberger
authors: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.|Department of Chemistry & Biochemistry, Department of Biomedical & Translational Sciences, College of Science and Mathematics, Rowan University , 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States.
authors: Thomas M
authors: TM
authors: Keck
authors: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.|Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine , 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
authors: Elie
authors: E
authors: Pommier
authors: Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine , 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
authors: Rana
authors: R
authors: Rais
authors: Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine , 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
authors: Barbara S
authors: BS
authors: Slusher
authors: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors: Eliot
authors: E
authors: Gardner
authors: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors: Zhi-Bing
authors: ZB
authors: You
authors: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors: Zheng-Xiong
authors: ZX
authors: Xi
authors: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors: Amy Hauck
authors: AH
authors: Newman
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D010098:Oxycodone; D051381:Rats; D020318:Rats, Long-Evans; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012457:Salicylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D018492:Dopamine Antagonists; D050637:Receptors, Dopamine D3; D012457:Salicylamides; D010098:Oxycodone; C045989:eticlopride