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

doi:10.5246/jcps.2019.03.015

Abstract

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

CLC Number:

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.

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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