title: Synthesis and biological evaluation of novel sigma-1 receptor antagonists based on pyrimidine scaffold as agents for treating neuropathic pain.
abstract: The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold was crucial for activity, and a basic amine was shown to be necessary according to the known pharmacophoric model. The most promising derivative was 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine (137), which exhibited a high binding affinity to σ1R receptor (Ki σ1 = 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivo tests, compound 137 exerted dose-dependent antinociceptive effects in mice formalin model and rats CCI models of neuropathic pain. In addition, no motor impairments were found in rotarod tests; acceptable pharmacokinetic properties were also noted. These data suggest compound 137 may constitute a novel class of drugs for the 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: Yu
authors.initials: Y
authors.lastname: Lan
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
authors.forename: Xudong
authors.initials: X
authors.lastname: Cao
authors.forename: Juecheng
authors.initials: J
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Xu
authors.forename: Yinli
authors.initials: Y
authors.lastname: Qiu
authors.forename: Tan
authors.initials: T
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Bi-Feng
authors.initials: BF
authors.lastname: Liu
authors.forename: Guisen
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000633:toxicity; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity; D009437:Neuralgia / Q000139:chemically induced / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D059226:Nociceptive Pain / Q000517:prevention & control*; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D002251:Carbon Tetrachloride; D051638:Ether-A-Go-Go Potassium Channels; D018696:Neuroprotective Agents; D010880:Piperidines; D011743:Pyrimidines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000595872:5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine; C030986:pyrimidine