Synthesis and Biological Evaluation of Novel σ1 Receptor Ligands for Treating Neuropathic Pain: 6‑Hydroxypyridazinones

• Published in: Journal of medicinal chemistry 2016-04, Vol.59 (7), p.2942-2961
• Main Authors: Cao, Xudong, Chen, Yin, Zhang, Yifang, Lan, Yu, Zhang, Juecheng, Xu, Xiangqing, Qiu, Yinli, Zhao, Song, Liu, Xin, Liu, Bi-Feng, Zhang, Guisen
• Format: Article
• Language: English
• Subjects: Analgesics, Non-Narcotic - chemical synthesis; Analgesics, Non-Narcotic - chemistry; Analgesics, Non-Narcotic - pharmacokinetics; Analgesics, Non-Narcotic - pharmacology; Animals; Chemistry Techniques, Synthetic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Formaldehyde - toxicity; Guinea Pigs; Ligands; Mice; Neuralgia - drug therapy; Pain Measurement - methods; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Rats, Sprague-Dawley; Receptors, Opioid, delta - metabolism; Rotarod Performance Test; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01416

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 (K i 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.