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Journal of Chinese Pharmaceutical Sciences ›› 2019, Vol. 28 ›› Issue (3): 160-166.DOI: 10.5246/jcps.2019.03.015

• Original articles • Previous Articles     Next Articles

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 Xie1,2, Xin Li2, Xiling Bian1, Qi Sun2*, Kewei Wang1,3*   

  1. 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).

Abstract:

A series of 1H-pyrrolo[3,2-b]pyridine (3a3f) and furo[3,2-b]pyridine derivatives (4a4g) 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-HT3A 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

CLC Number: 

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, JF = 247.5 Hz), 147.08, 143.11, 140.65, 130.48, 128.66 (d, JF = 2.8 Hz), 128.04 (d, JF = 8.3 Hz), 118.82, 117.13, 116.45 (d, JF = 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, JF = 250.5 Hz), 147.05, 135.13, 130.51 (d, JF = 8.5 Hz), 128.62 (d, JF = 3.0 Hz), 125.51 (d, JF = 3.1 Hz), 120.02 (d, JF = 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, JF = 251.5 Hz), 158.72, 148.98, 148.01, 146.08, 127.29 (d, JF = 8.4 Hz), 126.03 (d, JF = 3.3 Hz), 118.84, 117.82, 116.13 (d, JF = 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, JF = 254.5 Hz), 153.66 (d, JF = 3.2 Hz), 148.89, 147.36, 146.09, 130.78 (d, JF = 8.7 Hz), 126.96 (d, JF = 2.3 Hz), 124.54 (d, JF = 3.5 Hz), 119.22, 118.14 (d, JF = 22.2 Hz), 117.94, 116.35 (d, JF = 20.2 Hz), 107.45 (d, JF = 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, JF = 247.5 Hz), 158.17 (d, JF = 2.9 Hz), 148.70, 146.10, 146.08 (d, J = 2.2 Hz), 131.77 (d, JF = 8.4 Hz), 130.59 (d, JF = 8.4 Hz), 121.10, 121.03 (d, JF = 4.3 Hz), 117.88, 116.39 (d, JF = 21.2 Hz), 112.18 (d, JF = 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.