title: YQA14: a novel dopamine D3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D3 receptor-knockout mice.
abstract: The dopamine (DA) D3 receptor is posited to be importantly involved in drug reward and addiction, and D3 receptor antagonists have shown extraordinary promise as potential anti-addiction pharmacotherapeutic agents in animal models of drug addiction. SB-277011A is the best characterized D3 receptor antagonist in such models. However, the potential use of SB-277011A in humans is precluded by pharmacokinetic and toxicity problems. We here report a novel D3 receptor antagonist YQA14 that shows similar pharmacological properties as SB-277011A. In vitro receptor binding assays suggest that YQA14 has two binding sites on human cloned D3 receptors with K(i-High)  (0.68 × 10(-4)  nM) and K(i-Low)  (2.11 nM), and displays > 150-fold selectivity for D3 over D2 receptors and > 1000-fold selectivity for D3 over other DA receptors. Systemic administration of YQA14 (6.25-25 mg/kg) or SB-277011A (12.5-25 mg/kg) significantly and dose-dependently reduced intravenous cocaine self-administration under both low fixed-ratio and progressive-ratio reinforcement conditions in rats, while failing to alter oral sucrose self-administration and locomotor activity, suggesting a selective inhibition of drug reward. However, when the drug dose was increased to 50 mg/kg, YQA14 and SB-277011A significantly inhibited basal and cocaine-enhanced locomotion in rats. Finally, both D3 antagonists dose-dependently inhibited intravenous cocaine self-administration in wild-type mice, but not in D3 receptor-knockout mice, suggesting that their action is mediated by D3 receptor blockade. These findings suggest that YQA14 has a similar anti-addiction profile as SB-277011A, and deserves further study and development.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.forename: Ri-Fang
authors.initials: RF
authors.lastname: Yang
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.forename: Rui-Bin
authors.initials: RB
authors.lastname: Su
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Peng
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: József
authors.initials: J
authors.lastname: Gaál
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000517:prevention & control*; D003216:Conditioning, Operant / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles / Q000008:administration & dosage* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D011869:Radioligand Assay; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D012201:Reward; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D001583:Benzoxazoles; D018492:Dopamine Antagonists; D005449:Fluorenes; C116818:NGB 2904; D009570:Nitriles; D010879:Piperazines; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; C571881:YQA14; D019257:Quinpirole; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013395:Sucrose; D003042:Cocaine