A mimetic of the mSin3-binding helix of NRSF/REST ameliorates abnormal pain behavior in chronic pain models

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 20; pp. 4705 - 4709
• Main Authors: Ueda, Hiroshi, Kurita, Jun-ichi, Neyama, Hiroyuki, Hirao, Yuuka, Kouji, Hiroyuki, Mishina, Tadashi, Kasai, Masaji, Nakano, Hirofumi, Yoshimori, Atsushi, Nishimura, Yoshifumi
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.10.2017; Elsevier
• Subjects: Analgesics, Opioid - therapeutic use; Animals; Binding Sites; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Chronic Pain - drug therapy; Chronic Pain - pathology; Cold Temperature; Disease Models, Animal; Fibromyalgia; Heterocyclic Compounds, 2-Ring - chemistry; Heterocyclic Compounds, 2-Ring - metabolism; Heterocyclic Compounds, 2-Ring - therapeutic use; Life Sciences & Biomedicine; Mice; Molecular Docking Simulation; Morphine - therapeutic use; mSin3; Neuralgia - drug therapy; Neuralgia - pathology; Neuropathic pain; NMR; NRSF/REST; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Protein Domains; Protein Structure, Secondary; Repressor Proteins - chemistry; Repressor Proteins - metabolism; Science & Technology; MOPr; CSP; STD; NRSF/REST; PWL; nrse; Fibromyalgia; IPS; mSin3; Neuropathic pain; REST; NMR; NRSF; pSNL; PAH; ICS; HSQC; HDAC; re1; TARGET GENES; PROTEIN; WATERLOGSY; TRANSFER DIFFERENCE NMR; LIGAND; BINDING
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.09.006

[Display omitted] •Dysregulation of the neural repressor, NRSF is related to neuropathic pain.•Based on the structure of NRSF bound to mSin3, mS-11 was designed and synthesized.•NMR shows that the mS-11binding site on mSin3 is similar to that of NRSF.•mS-11 reverses hyposensitivity of the peripheral C-fiber response in neuropathy.•mS-11 reverses hypersensitivity of hyperalgesia/allodynia in a fibromyalgia model. The neuron-restrictive silencing factor NRSF/REST binds to neuron-restrictive silencing elements in neuronal genes and recruits corepressors such as mSin3 to inhibit epigenetically neuronal gene expression. Because dysregulation of NRSF/REST is related to neuropathic pain, here, we have designed compounds to target neuropathic pain based on the mSin3-binding helix structure of NRSF/REST and examined their ability to bind to mSin3 by NMR. One compound, mS-11, binds strongly to mSin3 with a binding mode similar to that of NRSF/REST. In a mouse model of neuropathic pain, mS-11 was found to ameliorate abnormal pain behavior and to reverse lost peripheral morphine analgesia. Furthermore, even in the less well epigenetically defined case of fibromyalgia, mS-11 ameliorated symptoms in a mouse model, suggesting that fibromyalgia is related to the dysfunction of NRSF/REST. Taken together, these findings show that the chemically optimized mimetic mS-11 can inhibit mSin3-NRSF/REST binding and successfully reverse lost peripheral and central morphine analgesia in mouse models of pain.