呋喃并[3,2-b]吡啶类化合物对α7尼古丁乙酰胆碱受体负向变构调节作用的电生理学评价

doi:10.5246/jcps.2019.03.015

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (3): 160-166.DOI: 10.5246/jcps.2019.03.015

呋喃并[3,2-b]吡啶类化合物对α7尼古丁乙酰胆碱受体负向变构调节作用的电生理学评价

王新童¹, 邹文星², 肖浩然², 谢文军^1,2, 李鑫², 卞希玲¹, 孙崎^2*, 王克威^1,3*

1. 北京大学医学部药学院分子与细胞药理学系, 北京 100191
2. 北京大学医学部药学院化学生物学系; 天然药物及仿生药物国家重点实验室, 北京 100191
3. 青岛大学药学院药理学系, 山东青岛 266021

收稿日期:2018-11-20 修回日期:2019-02-24 出版日期:2019-03-30 发布日期:2019-03-02
通讯作者: Tel.: +86-010-82805549; +86-532-82991070, E-mail: sunqi@bjmu.edu.cn; wangkw@qdu.edu.cn
基金资助:
National Natural Science Foundation (Grant No. 21572011, 81537410), and Ministry of Science and Technology (Grant No. 2014ZX09507003-006-004).

Electrophysiological characterization of furo[3,2-b]pyridine derivatives as negative allosteric modulator of a7 nicotinic acetylcholine receptor

Xintong Wang¹, Wenxing Zou², Haoran Xiao², Wenjun Xie^1,2, Xin Li², Xiling Bian¹, Qi Sun^2*, Kewei Wang^1,3*

1. Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
3. Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao 266021, China

Received:2018-11-20 Revised:2019-02-24 Online:2019-03-30 Published:2019-03-02
Contact: Tel.: +86-010-82805549; +86-532-82991070, E-mail: sunqi@bjmu.edu.cn; wangkw@qdu.edu.cn
Supported by:
National Natural Science Foundation (Grant No. 21572011, 81537410), and Ministry of Science and Technology (Grant No. 2014ZX09507003-006-004).

摘要/Abstract

摘要：

作者基于课题组先前得到的脱硫催化产物吡咯并[3,2-b]吡啶和呋喃并[3,2-b]吡啶类新型结构, 通过双电极电压钳电生理技术记录表达人源α7乙酰胆碱受体通道的非洲爪蟾卵母细胞对合成的化合物进行了活性评价。在100μM的乙酰胆碱作用下, 代表性呋喃并[3,2-b]吡啶化合物4f对α7烟碱型乙酰胆碱受体最大抑制率达87.8%和IC₅₀为5.51 μM。化合物4f对α7烟碱型乙酰胆碱受体具有亚型选择性, 是一类具有潜在研究价值的负向变构调节剂。

关键词: α7烟碱型乙酰胆碱受体, 负向变构调节剂, 吡咯并[3,2-b]吡啶, 呋喃并[3,2-b]吡啶

Abstract:

A series of 1H-pyrrolo[3,2-b]pyridine (3a–3f) and furo[3,2-b]pyridine derivatives (4a–4g) were evaluated on human α7 nicotinic acetylcholine receptors (nAChRs) using two-electrode voltage clamp (TEVC) recording. A representative 2-(2-methoxy-phenyl)-furo[3,2-b]pyridine 4f as negative allosteric modulator (NAM)selectively inhibited alpha7 nAChR over α3β4, α4β2 nAChRs and 5-HT_3A receptor, with a potency of IC₅₀ of 5.51 μM and a maximum inhibition rate of 87.8%. The preliminary analysis ofstructure-activity relationship (SAR) suggested that compound 4fcould serve as a basis for further discovery of potent and selective α7 nAChR NAMs.

Key words: α7 nAChR, Negative allosteric modulator, 1H-Pyrrolo[3,2-b]pyridine, Furo[3,2-b]pyridine derivatives

中图分类号:

R916

Supporting:

2-(p-Tolyl)-1H-pyrrolo[3,2-b]pyridine (3a)¹: Yield: 62%, 13mg. Yellow solid, m.p.: 232–234 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 11.70 (s, 1H), 8.29 (dd, J = 4.6, 1.2 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.08 (dd, J = 8.1, 4.6 Hz, 1H), 6.99 (d, J = 1.6 Hz, 1H), 2.36 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆): δ 146.59, 142.41, 142.18, 138.52, 130.58, 130.06, 129.10, 125.93, 119.15, 116.87, 98.44, 21.32.

2-(4-Fluorophenyl)-1H-Pyrrolo[3,2-b]pyridine (3b)¹: Yield: 54%, 11mg. Yellow solid, m.p.:201– 203 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 11.77 (s, 1H), 8.31 (dd, J = 4.6, 1.3 Hz, 1H), 8.02 – 7.95 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.9 Hz, 2H), 7.10 (dd, J = 8.1, 4.6 Hz, 1H), 7.04 (d, J = 1.7 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆): δ 162.56 (d, J_F = 247.5 Hz), 147.08, 143.11, 140.65, 130.48, 128.66 (d, J_F = 2.8 Hz), 128.04 (d, J_F= 8.3 Hz), 118.82, 117.13, 116.45 (d, J_F = 22.2 Hz), 99.42.

2-(4-Methoxylphenyl)-1H-pyrrolo[3,2-b]pyridine (3c)¹: Yield: 51%, 11mg; Yellow solid, m.p.: 208–210 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 11.80 (s, 1H), 8.30 (d, J = 4.2 Hz, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.14–7.04 (m, 3H) 6.95 (s, 1H), 3.83 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆): δ 160.05, 146.83, 142.28, 142.21, 130.50, 127.46, 124.45, 118.87, 116.59, 114.95, 97.79, 55.76.

2-(2-Fluorophenyl)-1H-pyrrolo[3,2-b]pyridine (3d)¹: Yield: 55%, 12mg. Yellow solid, m.p.: 135– 137 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 11.78 (s, 1H), 8.84–8.07 (m, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.85 (d, J = 1.9 Hz, 1H), 7.49–7.35 (m, 3H), 7.32–6.89 (m, 2H). ¹³C NMR (101 MHz, DMSO-d₆): δ 159.5 (d, J_F = 250.5 Hz), 147.05, 135.13, 130.51 (d, J_F = 8.5 Hz), 128.62 (d, J_F = 3.0 Hz), 125.51 (d, J_F = 3.1 Hz), 120.02 (d, J_F = 11.7 Hz), 118.65, 117.03 (d, J = 22.2 Hz), 116.28, 103.24 (d, J = 10.8 Hz).

2-(2-Thienyl)-1H-pyrrolo[3,2-b]pyridine (3e)¹: Yield: 49%, 10mg. Orange solid, m.p.: 266–267 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 11.87 (s, 1H), 8.31 (dd, J = 4.6, 1.1 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 4.3 Hz, 2H), 7.22–7.17 (m, 1H), 7.11 (dd, J = 8.1, 4.7 Hz, 1H), 6.82 (s, 1H). ¹³C NMR (101 MHz, DMSO-d₆): δ 146.83, 143.12, 136.35, 135.11, 130.25, 128.78, 127.06, 125.30, 118.68, 117.20, 99.13.

2-(Cyclohex-1-en-1-yl)-1H-pyrrolo[3,2-b]pyridine (3f)¹: Yield: 48%, 10mg. Yellow solid, m.p.: 134– 135 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 11.26 (s, 1H), 8.23 (dd, J = 4.6, 1.1 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.03 (dd, J = 8.1, 4.6 Hz, 1H), 6.49 (dd, J = 9.7, 5.8 Hz, 2H), 2.43 (d, J = 1.5 Hz, 2H), 2.27–2.18 (m, 2H), 1.74 (dd, J = 7.6, 3.7 Hz, 2H), 1.64 (dd, J = 7.6, 3.7 Hz, 2H). ¹³C NMR (101 MHz, DMSO-d₆): δ 147.19, 143.25, 142.57, 129.87, 129.03, 125.07, 117.80, 116.71, 98.50, 25.88, 25.45, 22.56, 22.17.

2-(4-Tolyl)-furo[3,2-b]pyridine (4a)¹: Yield: 55%, 12 mg. Yellow solid, m.p.: 123–125 °C. ¹H NMR (400 MHz, CDCl₃): δ 9.06–8.19 (m, 1H), 7.81 (d, J = 7.9 Hz, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.19 (s, 2H), 2.43 (s, 3H). ¹³C NMR (101 MHz, CDCl₃): δ 159.96, 149.25, 145.81, 139.83, 129.64, 126.98, 125.28, 118.85, 117.60, 101.71, 21.48.

2-(4-Fluorophenyl)-furo[3,2-b]pyridine (4b)¹: Yield: 50%, 11 mg. Yellow solid, m.p.: 113–115 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.55 (s, 1H), 7.97–7.83 (m, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.20 (dd, J = 14.2, 5.6 Hz, 4H). ¹³C NMR (101 MHz, CDCl₃): δ 163.48 (d, J_F = 251.5 Hz), 158.72, 148.98, 148.01, 146.08, 127.29 (d, J_F = 8.4 Hz), 126.03 (d, J_F = 3.3 Hz), 118.84, 117.82, 116.13 (d, J_F = 22.2 Hz), 102.14.

2-(2-Fluorophenyl)-furo[3,2-b]pyridine (4c)¹: Yield: 75%, 16 mg. Yellow solid, m.p.: 79–81 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.68–8.52 (m, 1H), 8.12–8.02 (m, 1H), 8.02–7.93 (m, 1H), 7.62–7.54 (m, 1H), 7.50–7.42 (m, 1H), 7.39 (dd, J = 8.1, 5.1 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.24 (dd, J=14.1, 5.6 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃): δ 159.89 (d, J_F = 254.5 Hz), 153.66 (d, J_F = 3.2 Hz), 148.89, 147.36, 146.09, 130.78 (d, J_F = 8.7 Hz), 126.96 (d, J_F = 2.3 Hz), 124.54 (d, J_F = 3.5 Hz), 119.22, 118.14 (d, J_F = 22.2 Hz), 117.94, 116.35 (d, J_F = 20.2 Hz), 107.45 (d, J_F = 12.7 Hz).

2-(2-Thienyl)-furo[3,2-b]pyridine (4d)¹: Yield: 74%, 15 mg. Orange solid, m.p.: 74–76 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.75–8.33 (m, 1H), 7.75 (dd, J = 19.0, 4.7 Hz, 1H), 7.60 (d, J = 3.1 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.26–7.18 (m, 1H), 7.15 (dd, J = 10.3, 5.7 Hz, 1H), 7.11 (s, 1H). ¹³C NMR (101 MHz, CDCl₃): δ 155.44, 148.45, 147.92, 145.39, 132.24, 128.22, 127.59, 126.25, 118.82, 118.13, 101.57.

2-(3-Fluorophenyl)-furo[3,2-b]pyridine (4e)¹: Yield: 53%, 11 mg. Yellow solid, m.p.: 107–108 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.57 (d, J = 4.2 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.67–7.57 (m, 1H), 7.47 (td, J = 8.0, 5.9 Hz, 1H), 7.28 (d, J = 0.8 Hz, 2H), 7.20–7.06 (m, 1H). ¹³C NMR (101 MHz, CDCl₃): δ 163.11 (d, J_F = 247.5 Hz), 158.17 (d, J_F = 2.9 Hz), 148.70, 146.10, 146.08 (d, J = 2.2 Hz), 131.77 (d, J_F = 8.4 Hz), 130.59 (d, J_F = 8.4 Hz), 121.10, 121.03 (d, J_F = 4.3 Hz), 117.88, 116.39 (d, J_F = 21.2 Hz), 112.18 (d, J_F = 24.2 Hz), 103.51.

2-(2-Methoxyphenyl)-furo[3,2-b]pyridine (4f)¹: Yield: 45%, 11mg. Yellow solis, m.p.: 77–78 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.57 (s, 1H), 8.08 (dd, J = 7.8, 1.4 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.45–7.35 (m, 1H), 7.23 (dd, J = 7.2, 4.5 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 4.02 (s, 3H). ¹³C NMR (101 MHz, CDCl₃): δ 157.02, 156.00, 149.58, 145.61, 130.93, 130.45, 126.97, 120.74, 118.64, 118.58, 117.40, 111.20, 107.30, 55.54.

2-Phenyl-furo[3,2-b]pyridine (4g)¹: Yield: 77%, 15 mg. Yellow solid, m.p.: 88–89 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 8.52 (dd, J = 4.7, 1.1 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.02–7.93 (m, 2H), 7.67 (s, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.47 (t, J = 7.3 Hz, 1H), 7.33 (dd, J = 8.3, 4.7 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆): δ 159.33, 148.87, 147.90, 146.62, 130.22, 129.62, 129.60, 125.56, 119.80, 118.59, 103.30.

Reference

1. Zou, W.X.; Huang, Z.Z.; Jiang, K.; Wu, Y.; Xue, Y.Q.; Suzenet, F.; Sun, Q; Guillaumet, G; Chelation-assisted C-S activation/cascade heteroannulation ofpyridine-2-thione derivatives in Pd-catalyzed cross-coupling reaction with alkynes. Tetrahedron 2017, 73, 5485 –5492.

王新童, 邹文星, 肖浩然, 谢文军, 李鑫, 卞希玲, 孙崎, 王克威. 呋喃并[3,2-b]吡啶类化合物对α7尼古丁乙酰胆碱受体负向变构调节作用的电生理学评价[J]. 中国药学(英文版), 2019, 28(3): 160-166.

Xintong Wang, Wenxing Zou, Haoran Xiao, Wenjun Xie, Xin Li, Xiling Bian, Qi Sun, Kewei Wang. Electrophysiological characterization of furo[3,2-b]pyridine derivatives as negative allosteric modulator of a7 nicotinic acetylcholine receptor[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(3): 160-166.

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呋喃并[3,2-b]吡啶类化合物对α7尼古丁乙酰胆碱受体负向变构调节作用的电生理学评价

Electrophysiological characterization of furo[3,2-b]pyridine derivatives as negative allosteric modulator of a7 nicotinic acetylcholine receptor

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