Discovery of novel and orally active NR2B-selective N-methyl-D-aspartate (NMDA) antagonists, pyridinol derivatives with reduced HERG binding affinity.

Kawai M; Nakamura H; Sakurada I; Shimokawa H; Tanaka H; Matsumizu M; Ando K; Hattori K; Ohta A; Nukui S; Omura A; Kawamura M

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Discovery of novel and orally active NR2B-selective N-methyl-D-aspartate (NMDA) antagonists, pyridinol derivatives with reduced HERG binding affinity.

机译：发现新型和口服活性的NR2B选择性N-甲基-D-天冬氨酸（NMDA）拮抗剂，具有降低的HERG结合亲和力的吡啶醇衍生物。

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Novel NR2B antagonists with an amide tether were found by an approach to avoid pharmacophoric similarity to dofetilide. Structure-activity relationship investigation led to N-[cis-4-hydroxy-4-(5-hydroxypyridin-2-yl)cyclohexyl]-3-henylpropanamide as an orally active NR2B-subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist with very weak HERG (human ether-a-go-go related gene) binding (IC(50)> 30 microM). This compound exhibited potent in vivo anti-allodynic activity in the mouse partial sciatic nerve ligation (PSL) model (minimum effective dose=10 mg/kg, po).

机译：通过避免与多非利特的药效学相似性的方法，发现了具有酰胺系链的新型NR2B拮抗剂。结构-活性关系研究导致N- [顺式-4-羟基-4-（5-羟基吡啶-2-基）环己基] -3-henylpropanamide作为口服活性NR2B亚型选择性N-甲基-D-天冬氨酸（NMDA））受体拮抗剂，具有非常弱的HERG（人类醚-go-go-go相关基因）结合（IC（50）> 30 microM）。该化合物在小鼠部分坐骨神经结扎（PSL）模型（最小有效剂量= 10 mg / kg，口服）中显示出强大的体内抗痛觉过敏活性。

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来源
《Bioorganic and Medicinal Chemistry Letters》 |2007年第20期|共4页
作者
Kawai M; Nakamura H; Sakurada I; Shimokawa H; Tanaka H; Matsumizu M; Ando K; Hattori K; Ohta A; Nukui S; Omura A; Kawamura M;
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正文语种 eng
中图分类药学;生物化学;
关键词
binding; antagonists; Aspartate;

机译：结合剂;拮抗剂;天冬氨酸;

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1. Discovery of novel and orally active NR2B-selective N-methyl-D-aspartate (NMDA) antagonists, pyridinol derivatives with reduced HERG binding affinity. [J] . Kawai M, Nakamura H, Sakurada I, Bioorganic and Medicinal Chemistry Letters . 2007,第20期

机译：发现新型和口服活性的NR2B选择性N-甲基-D-天冬氨酸（NMDA）拮抗剂，具有降低的HERG结合亲和力的吡啶醇衍生物。
2. Discovery of 5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzy1)-2-imino-1,2-dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active alpha(1D) Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities [J] . Sakauchi Nobuki, Kohara Yasuhisa, Sato Ayumu, Journal of Medicinal Chemistry . 2016,第7期

机译：发现5-氯-1-（5-氯-2-（甲基磺酰基）benzy1）-2-亚氨基-1,2-二氢吡啶-3-羧酰胺（TAK-259）为新型，选择性和口服活性α（ 1D）具有抗尿频效应的肾上腺素能受体拮抗剂：减少人类以太相关基因（hERG）的责任
3. Discovery of (-)-6-(2-(4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl)-1-hydroxyethyl)-3,4-dihydro -2(1H)-quinolinone--a potent NR2B-selective N-methyl D-aspartate (NMDA) antagonist for the treatment of pain. [J] . Kawai M, Ando K, Matsumoto Y, Bioorganic and Medicinal Chemistry Letters . 2007,第20期

机译：发现（-）-6-（2-（4-（3-（氟代苯基）-4-羟基-1-哌啶基）-1-羟乙基）-3,4-二氢-2（1H）-喹啉酮-一种有效的NR2B选择性N-甲基D-天冬氨酸（NMDA）拮抗剂，用于治疗疼痛。
4. Edible Biologics: Orally Active Peptide Bradykinin B1 Receptor Antagonists for Inflammatory Pain Treatment [C] . James P. Tam, Clarence T.T. Wong Chinese International Peptide Symposium . 2013

机译：食用生物学：口服活性肽Bradykinin B1受体拮抗剂用于炎症疼痛治疗
5. Effect of chronic ethanol exposure on the expression of the N-methyl-D-aspartate (NMDA) receptor 2C subunit and on MK-801 binding sites in the cerebral cortex of the near-term fetal guinea pig. [D] . Chiu, Joanne Wing-Yan. 1997

机译：长期乙醇暴露对近期胎鼠豚鼠大脑皮层N-甲基-D-天冬氨酸（NMDA）受体2C亚单位表达和MK-801结合位点的影响。
6. Amygdala infusions of an NR2B-selective or an NR2A-preferring NMDA receptor antagonist differentially influence fear conditioning and expression in the fear-potentiated startle test [O] . David L. Walker, Michael Davis 2008

机译：杏仁核输注的NR2B选择性或NR2A优先的NMDA受体拮抗剂在恐惧增强的惊吓测试中差异地影响恐惧条件和表达。
7. Dextromethorphan/Bupropion: A Novel Oral NMDA (N-methyl-d-aspartate) Receptor Antagonist with Multimodal Activity [O] . Stephen M. Stahl 2019

机译：Dextromethorphan / Bupropion：一种新的口服NMDA（N-甲基-D-天冬氨酸）受体拮抗剂，具有多式联运活性
8. NMDA (N-Methyl-D-Aspartate)-Receptor Antagonist, MK-801, Suppresses Limbic Kindling and Kindled Seizures [R] . Gilbert, M. E. 1988

机译：NmDa（N-甲基-D-天冬氨酸） - 受体拮抗剂，mK-801，抑制边缘点燃和点燃癫痫发作

Discovery of novel and orally active NR2B-selective N-methyl-D-aspartate (NMDA) antagonists, pyridinol derivatives with reduced HERG binding affinity.

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