title: Synthesis and Biological Evaluation of Novel σ1 Receptor Ligands for Treating Neuropathic Pain: 6-Hydroxypyridazinones.
abstract: By use of the 6-hydroxypyridazinone framework, a new series of potent σ1 receptor ligands associated with pharmacological antineuropathic pain activity was synthesized and is described in this article. In vitro receptor binding studies revealed high σ1 receptor affinity (Ki σ1 = 1.4 nM) and excellent selectivity over not only σ2 receptor (1366-fold) but also other CNS targets (adrenergic, μ-opioid, sertonerigic receptors, etc.) for 2-(3,4-dichlorophenyl)-6-(3-(piperidin-1-yl)propoxy)pyridazin-3(2H)-one (compound 54). Compound 54 exhibited dose-dependent antiallodynic properties in mouse formalin model and rats chronic constriction injury (CCI) model of neuropathic pain. In addition, functional activity of compound 54 was evaluated using phenytoin and indicated that the compound was a σ1 receptor antagonist. Moreover, no motor impairments were found in rotarod tests at antiallodynic doses and no sedative side effect was evident in locomotor activity tests. Last but not least, good safety and favorable pharmacokinetic properties were also noted. These profiles suggest that compound 54 may be a member of a novel class of candidate drugs for treatment of neuropathic pain.
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan 430074, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Cao
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd. , 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan 430074, China.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan 430074, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lan
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan 430074, China.
authors.forename: Juecheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd. , 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd. , 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
authors.forename: Yinli
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd. , 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan 430074, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan 430074, China.
authors.forename: Bi-Feng
authors.initials: BF
authors.lastname: Liu
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan 430074, China.|Jiangsu Nhwa Pharmaceutical Co., Ltd. , 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
authors.forename: Guisen
authors.initials: G
authors.lastname: Zhang
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005557:Formaldehyde / Q000633:toxicity; D006168:Guinea Pigs; D008024:Ligands; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy*; D010147:Pain Measurement / Q000379:methods; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D045442:Rotarod Performance Test; D013329:Structure-Activity Relationship
chemical_list: C000610597:2-(3,4-dichlorophenyl)-6-(3-(piperidin-1-yl)propoxy)pyridazin-3(2H)-one; D018712:Analgesics, Non-Narcotic; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D008024:Ligands; D011724:Pyridazines; D017465:Receptors, Opioid, delta; D005557:Formaldehyde