3H-喹唑啉-4-酮衍生物的设计、合成及其α7尼古丁乙酰胆碱受体正向变构调节作用评价

doi:10.5246/jcps.2018.08.055

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (8): 540-552.DOI: 10.5246/jcps.2018.08.055

3H-喹唑啉-4-酮衍生物的设计、合成及其α7尼古丁乙酰胆碱受体正向变构调节作用评价

黄宗泽¹, 王新童², 孟盈¹, 李鑫¹, 肖浩然¹, 卞希玲², 王克威^2,3*, 孙崎^1*

1. 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
2. 北京大学医学部药学院分子与细胞药理学系, 北京 100191
3. 青岛大学药学院药理学系, 山东青岛 266021

收稿日期:2018-04-23 修回日期:2018-05-28 出版日期:2018-09-04 发布日期:2018-06-13
通讯作者: Tel.: +86-532-82991070; +86-010-82801504, E-mail: wangkw@qdu.edu.cn; sunqi@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (NSFC, Grant No. 21572011) and Ministry of Science and Technology of China (Grant No. 2013CB531302).

The design, synthesis and α7 nicotinic acetylcholine receptors positive allosteric modulative evaluation of 3H-quinazolin-4-one derivatives

Zongze Huang¹, Xintong Wang², Ying Meng¹, Xin Li¹, Haoran Xiao¹, Xiling Bian², KeWei Wang^2,3*, Qi Sun^1*

1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Department of Molecular and cellular Pharmacology, 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:2018-04-23 Revised:2018-05-28 Online:2018-09-04 Published:2018-06-13
Contact: Tel.: +86-532-82991070; +86-010-82801504, E-mail: wangkw@qdu.edu.cn; sunqi@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (NSFC, Grant No. 21572011) and Ministry of Science and Technology of China (Grant No. 2013CB531302).

摘要/Abstract

摘要：

作者基于课题组先前得到的具有较强α7烟碱型乙酰胆碱受体I型正向变构调节剂活性的先导化合物2, 设计并合成了一系列的6位取代的3H-喹唑啉-4-酮化合物(3a−3d), 所有目标化合物均通过对表达有人源α7乙酰胆碱受体的非洲爪蟾卵使用双电极电压钳技术来进行活性评价。然而, 在100 μM的乙酰胆碱作用下, 所有化合物均没有显示出比先导化合物2更高的活性。由此证明噻唑[4,5-d]并嘧啶-7(6H)-酮母核是发挥正向变构调节活性的必需基团, 是对先导化合物2的构效关系的补充。

关键词: 3H-喹唑啉-4-酮, α7烟碱型乙酰胆碱受体, 正向变构调节剂, 构效关系, 阿尔兹海默综合症

Abstract:

A series of new 6-substituted 3H-quinazolin-4-ones (3a−3d) were designed, synthesized and evaluated as the type I positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus ooctyes by two-electrode voltage clamp. However, no compound showed a better efficacious PAM than lead compound 2 in the presence of acetylcholine (100 μM). The structure-activity relationship (SAR) analysis suggested that thiazolo[4,5-d]pyrimidin-7(6H)-one was the key biological skeleton.

Key words: 3H-Quinazolin-4-ones, α7 nAChR, Positive allosteric modulators, Structure-activity relationship, Schizophrenia disease

中图分类号:

R916.4

Supporting:

黄宗泽, 王新童, 孟盈, 李鑫, 肖浩然, 卞希玲, 王克威, 孙崎. 3H-喹唑啉-4-酮衍生物的设计、合成及其α7尼古丁乙酰胆碱受体正向变构调节作用评价[J]. 中国药学(英文版), 2018, 27(8): 540-552.

Zongze Huang, Xintong Wang, Ying Meng, Xin Li, Haoran Xiao, Xiling Bian, KeWei Wang, Qi Sun. The design, synthesis and α7 nicotinic acetylcholine receptors positive allosteric modulative evaluation of 3H-quinazolin-4-one derivatives[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(8): 540-552.

参考文献

[1] (a) Jensen, A.A.; Frlund, B.; Liljefors, T.; Krogsgaard-Larsen, P. Neuronal nicotinic acetylcholine receptors: Structural revelations, target identifications, and therapeutic inspirations. J. Med. Chem. 2005, 48, 4705−4745. (b) Gotti, C.; Riganti, L.; Vailati, S.; Clementi, F. Brain neuronal nicotinic receptors as new targets for drug discovery. Curr. Pharm. Des. 2006, 12, 407−428. (c) Briggs, C.A.; Grønlien, J.H.; Curzon, P.; Timmermann, D.B.; Ween, H.; Thorin-Hagene, K.; Kerr, P.; Anderson, D. J.; Malysz, J.; Dyhring, T.; Olsen, G.M.; Peters, D.; Bunnelle, W.H.; Gopalakrishnan, M. Role of channel activation in cognitive enhancement mediated by α7 nicotinic acetylcholine receptors. Br. J. Pharmacol. 2009, 158, 1486−1494. (d) Hajós, M.; Rogers, B.N. Targeting α7 nicotinic acetylcholine receptors in the treatment of schizophrenia. Curr. Pharm. Des. 2010, 16, 538−554.

[2] (a) Seguela, P.; Wadiche, J.; Dineley-Miller, K.; Dani, J.A.; Patrick, J.W. Molecular cloning, functional properties, and distribution of rat brain alpha 7: A nicotinic cation channel highly permeable to calcium. J. Neurosci. 1993, 13, 596−604. (b) Gotti, C.; Clementi, F.; Fornari, A.; Gaimarri, A.; Guiducci, S.; Manfredi, I.; Moretti, M.; Pedrazzi, P.; Pucci, L.; Zoli, M. Structural and functional diversity of native brain neuronal nicotinic receptors. Biochem. Pharmacol. 2009, 78, 703−711.

[3] (a) Xie, X.; Zhang, G.; Zhang, L. Advances on α7 nAChR as targets for drug development. Chin. J. Med. Chem. 2015, 25, 313‒323. (b) Hauser, T.A.; Kucinski, A.; Jordan, K.G.; Gatto, G.J.; Wersinger, S.R.; Hesse, R.A.; Stachowiak, E.K.; Stachowiak, M.K.; Papke, R.L.; Lippiello, P.M.; Bencherif, M. TC-5619: An alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia. Biochem. Pharmacol. 2013, 355, 32‒37. (c) Wishka, D.G.; Walker, D.P.; Yates, K.M.; Reitz, S.C.; Jia, S.; Myers, J.K.; Olson, K.L.; Jacobsen, E.J.; Wolfe, M.L.; Groppi, V.E.; Hanchar, A.J.; Thornburgh, B.A.; Cortes-Burgos, L.A.; Wong, E.H.F.; Staton, B.A.; Raub, T.J.; Higdon, N.R.; Wall, T.M.; Hurst, R.S.; Walters, R.R.; Hoffmann, W.E.; Hajos, M.; Franklin, S.; Carey, G.; Gold, L.H.; Cook, K.K.; Sands, S.B.; Zhao, S.X.; Soglia, J.R.; Kalgutkar, A.S.; Arneric, S.P.; Rogers, B.N. Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, An agonist of the α7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: Synthesis and structure-activity relationship. J. Med. Chem. 2006, 49, 4425‒4436.

[4] Preskorn, S.H.; Gawryl, M.; Dgetluck, N. Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia. J. Psychiatr. Pract. 2014, 20, 12‒24.

[5] (a) Williams, D.K.; Wang, J.; Papke, R.L. Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: Advantages and limitations. Biochem. Pharmacol. 2011, 82, 915−930. (b) Pandya, A.A.; Yakel, J.L. Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies. Biochem. Pharmacol. 2013, 86, 1054−1062.

[6] (a) Faghih, R.; Gopalakrishnan, M.; Briggs, C.A. Allosteric modulators of the α7 nicotinic acetylcholine receptor. J. Med. Chem. 2008, 51, 701−712. (b) Grønlien, J.H.; Hakerud, M.; Ween, H.; Thorin-Hagene, K.; Briggs, C.A.; Gopalakrishnan, M.; Malysz, J. Distinct profiles of α7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Mol. Pharmacol. 2007, 72, 715−724. (c) Potasiewicz, A.; Hołuj, M.; Kos, T.; Popik, P.; Arias, H.R.; Nikiforuk, A. 3-Furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the a7 nicotinic receptor, reverses schizophrenia-like cognitive and social deficits in rats. Neuropharmacol. 2017, 113(Part A), 188–197.

[7] Guerra-Álvarez, M.; Moreno-Ortega, A.J.; Navarro, E.; Fernández-Morales, J.C.; Egea, J,; López, M.G.; Cano-Abad, M.F. Positive allosteric modulation of alpha-7 nicotinic receptors promotes cell death by inducing Ca2+ release from the endoplasmic reticulum. J. Neurochem. 2015, 133, 309−319.

[8] (a) Gotti, C.; Clementi, F.; Zoli, M. Brain nicotinic acetylcholine receptors: Native subtypes and their relevance. Trends Pharmacol. Sci. 2006, 27, 482‒491. (b) Sharma, G.; Vijayaraghavan, S. Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores. Proc. Natl. Acad. Sci. USA. 2001, 98, 4148‒4153. (c) Yakel J.L. Nicotinic ACh receptors in the hippocampal circuit; functional expression and role in synaptic plasticity. J. Physiol. 2014, 592, 4147‒4153.

[9] (a) Krause, R.M.; Buisson, B.; Bertrand, S.; Corringer, P.J.; Galzi, J.L.; Changeux, J.P.; Bertrand, D. Ivermectin: A positive allosteric effector of the α7 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 1998, 53, 283‒294. (b) Lopes, C.; Pereira, E.F.; Wu, H.Q.; Purushottamachar, P.; Njar, V.; Schwarcz, R.; Albuquerque, E.X. Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at α7 nicotinic receptors. J. Pharmacol. Exp. Ther. 2007, 322, 48‒58. (c) Zwart, R.; Filippi, G.D.; Broad, L.M.; McPhie, G.I.; Pearson, K.H.; Baldwinson, T.; Sher, E. 5-Hydroxyindole potentiates human α7 nicotinic receptor-mediated responses and enhances acetylcholine-induced glutamate release in cerebellar slices. Neuropharmacology. 2002, 43, 374‒384. (d) Grønlien, J.H.; Håkerud, M.; Ween, H.; Thorin-Hagene, K.; Briggs, C.A.; Gopalakrishnan, M.; Malysz, J. Distinct profiles of α7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Mol. Pharmacol. 2007, 72, 715‒724. (e) Ng, H.J.; Whittemore, E.R.; Tran, M.B.; Hogenkamp, D.J.; Broide, R.S.; Johnstone, T.B.; Zheng, L.; Stevens, K.E.; Gee, K.W. Nootropic α7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators. Proc. Natl. Acad. Sci. USA. 2007, 104, 8059‒8064. (f) Timmermann, D.B.; Grønlien, J.H.; Kohlhaas, K.L.; Nielsen, E.Ø.; Dam, E.; Jørgensen, T.D.; Ahring, P.K.; Peters, D.; Holst, D.; Chrsitensen, J.K.; Malysz, J.; Briggs, C.A.; Gopalakrishnan, M.; Olsen, G.M. An allosteric modulator of the α7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo. J. Pharmacol. Exp. Ther. 2007, 323, 294‒307. (g) Dunlop, J.; Lock, T.; Jow, B.; Sitzia, F.; Grauer, S.; Jow, F.; Kramer, A.; Bowlby, M.R.; Randall, A.; Kowal, D.; Gilbert, A.; Comery, T.A.; LaRocque, J.; Soloveva, V.; Brown, J.; Roncarati, R. Old and new pharmacology: Positive allosteric modulation of the α7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']dipyrrole-1(2H)-carboxamide). J. Pharmacol. Exp. Ther. 2009, 328, 766‒776. (h) Broad, L.M.; Zwart, R.; Pearson, K.H.; Lee, M.; Wallace, L.;McPhie, G.I.; Emkey, R.; Hollinshead, S.P.; Dell, C.P.; Baker, S.R.; Sher, E. Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators. J. Pharmacol. Exp. Ther. 2006, 318, 1108‒1117.

[10] (a) Huang, X.; Jiao, W.; Sun, Q.; Wang, K. Pharmacokinetic characterization of a novel α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator LD486 in rat plasma using a validated LC-MS/MS assay. J. Chin. Pharm. Sci. 2016, 25, 517–525. (b) Wang, K.; Sun, Q.; Jiao, W.; Tang, J. Preparation of thiazolopyrimidinone compound and their medical use. Faming Zhuanli Shenqing. 2017, CN 106279211 A 20170104 (Patent in Chinese).

[11] Li, Y.H.; Sun, L.L.; Yang. T.Y.; Jiao, W.X.; Tang, J.S.; Huang, X.M.; Huang, Z.Z.; Meng, Y.; Luo, L.C.; Wang, X.T.; Bian, X.L.; Zhang, F.; Sun, Q.; Wang, K.W. Design and synthesis of novel positive allosteric modulators of alpha7 nicotinic acetylcholine receptors with the ability to rescue auditory gating deficit in mice. J. Med. Chem. 2018, DOI: 10.1021/acs.jmedchem.7b01492.

[12] De Lucca, G.V.; Shi, Q.; Liu, Q. Small Molecule reversible inhibitors of Bruton's tyrosine kinase (BTK): Structure-activity relationships leading to the identification of 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177). J. Med. Chem. 2016, 59, 7915–7935.

[13] Zhang, H.; Cai, Q.; Ma, D. Amino acid promoted CuI-catalyzed C-N bond formation between aryl halides and amines or N-containing heterocycles. J. Org. Chem. 2005, 70, 5164–5173.

[14] Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Efficient Copper(I)-catalyzed C–S cross coupling of thiols with aryl halides in water. Eur. J. Org. Chem. 2008, 4, 640–643.

[15] Kabir, M.S.; Lorenz, M.; Van Linn, M.L. A very active Cu-catalytic system for the synthesis of aryl, heteroaryl, and vinyl sulfides. J. Org. Chem. 2010, 75, 3626–3643.

[16] Cameron, K.O.; Kung, D.W.; Kalgutkar, A.S. Discovery and preclinical characterization of 6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid (PF-06409577), a direct activator of adenosine monophosphate-activated protein kinase (AMPK), for the potential treatment of diabetic nephropathy. J. Med. Chem. 2016, 59, 8068–8081.

[17] Tang, J.; Xie, B.; Bian, X.; Xue, Y.; Wei, N.; Zhou, J.; Hao, Y.; Li, Gang.; Zhang, L.; Wang, K. Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B. Acta Pharmacol. Sin. 2015, 36, 800–812.

3H-喹唑啉-4-酮衍生物的设计、合成及其α7尼古丁乙酰胆碱受体正向变构调节作用评价

The design, synthesis and α7 nicotinic acetylcholine receptors positive allosteric modulative evaluation of 3H-quinazolin-4-one derivatives

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