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Structure-Based Design of Novel Biphenyl Amide Antagonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 8 Channels with Potential Implications in the Treatment of Sensory Neuropathies.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-01-09 , DOI: 10.1021/acschemneuro.9b00404
V Blair Journigan 1, 2 , Zhiwei Feng 3, 4, 5 , Saifur Rahman 6 , Yuanqiang Wang 3, 4, 5 , A R M Ruhul Amin 1, 2 , Colleen E Heffner 1 , Nicholas Bachtel 1 , Siyi Wang 3, 4, 5 , Sara Gonzalez-Rodriguez 7 , Asia Fernández-Carvajal 7 , Gregorio Fernández-Ballester 7 , Jacob K Hilton 8, 9, 10 , Wade D Van Horn 8, 9, 10 , Antonio Ferrer-Montiel 7 , Xiang-Qun Xie 3, 4, 5 , Taufiq Rahman 6
Affiliation  

Structure-activity relationship studies of a reported menthol-based transient receptor potential cation channel subfamily M member 8 channel (TRPM8) antagonist, guided by computational simulations and structure-based design, uncovers a novel series of TRPM8 antagonists with >10-fold selectivity versus related TRP subtypes. Spiro[4.5]decan-8-yl analogue 14 inhibits icilin-evoked Ca2+ entry in HEK-293 cells stably expressing human TRPM8 (hTRPM8) with an IC50 of 2.4 ± 1.0 nM, while in whole-cell patch-clamp recordings this analogue inhibits menthol-evoked currents with a hTRPM8 IC50 of 64 ± 2 nM. Molecular dynamics (MD) simulations of compound 14 in our homology model of hTRPM8 suggest that this antagonist forms extensive hydrophobic contacts within the orthosteric site. In the wet dog shakes (WDS) assay, compound 14 dose-dependently blocks icilin-triggered shaking behaviors in mice. Upon local administration, compound 14 dose dependently inhibits cold allodynia evoked by the chemotherapy oxaliplatin in a murine model of peripheral neuropathy at microgram doses. Our findings suggest that 14 and other biphenyl amide analogues within our series can find utility as potent antagonist chemical probes derived from (-)-menthol as well as small molecule therapeutic scaffolds for chemotherapy-induced peripheral neuropathy (CIPN) and other sensory neuropathies.

中文翻译:

人瞬态受体潜在阳离子通道亚家族M成员8通道的新型联苯酰胺拮抗剂的基于结构的设计,在感觉神经病的治疗中具有潜在的意义。

报道的基于薄荷醇的瞬时受体潜在阳离子通道亚家族M成员8通道(TRPM8)拮抗剂的结构活性关系研究,在计算模拟和基于结构的设计的指导下,发现了一系列新的TRPM8拮抗剂,其选择性> 10倍。相关的TRP亚型。Spiro [4.5] decan-8-yl类似物14抑制伊西林诱发的Ca2 +进入稳定表达人TRPM8(hTRPM8)的HEK-293细胞,IC50为2.4±1.0 nM,而在全细胞膜片钳记录中,该类似物抑制薄荷醇诱发的电流,hTRPM8 IC50为64±2 nM。在我们的hTRPM8同源模型中,化合物14的分子动力学(MD)模拟表明,该拮抗剂在正构位点内形成广泛的疏水性接触。在湿狗摇(WDS)分析中,化合物14剂量依赖性地阻断了西西林触发的小鼠摇动行为。局部给药后,化合物14剂量依赖性地抑制微克剂量的周围神经病的鼠模型中由化学疗法奥沙利铂引起的感性异常性疼痛。我们的发现表明,我们系列中的14种和其他联苯酰胺类似物可以用作衍生自(-)-薄荷醇以及小分子治疗支架的有效拮抗剂化学探针,用于化学疗法诱发的周围神经病(CIPN)和其他感觉神经病。
更新日期:2020-01-09
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