Sonogashira coupling reaction in the synthesis of novel positive allosteric modulators of α7 nicotinic acetylcholine receptors

doi:10.5246/jcps.2022.05.033

Journal of Chinese Pharmaceutical Sciences ›› 2022, Vol. 31 ›› Issue (5): 374-381.DOI: 10.5246/jcps.2022.05.033

• Original articles • Previous Articles Next Articles

Sonogashira coupling reaction in the synthesis of novel positive allosteric modulators of α7 nicotinic acetylcholine receptors

Wenjun Xie¹^,², Haoran Xiao¹, Xintong Wang², Zongze Huang¹, Xiling Bian², Kewei Wang²^,³^,^*(), Qi Sun¹^,^*()

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:2021-12-15 Revised:2022-01-08 Accepted:2022-02-20 Online:2022-06-02 Published:2022-06-02
Contact: Kewei Wang, Qi Sun

Abstract

Abstract:

A series of 2-arylamino-1,3,5-triazine derivatives (4a–4g), which were designed and synthesized via Sonogashira coupling reaction, were evaluated using two-electrode voltage clamp (TEVC) recordings of human α7 nAChR expressed in Xenopus ooctyes. Compound 4g as a positive allosteric modulator (PAM) showed better efficacy than lead compound 3 (HZZ-A-11) with an EC₅₀ value of 1.23 ± 0.41 μM. Further pharmacological evaluation of compound 4g might lead to the developmental potential for therapy of cognitive deficits commonly shared by neuropsychiatric disorders, such as schizophrenia and Alzheimer’s disease.

Key words: Cognitive deficit, α7 nAChR, Positive allosteric modulators, Sonogashira coupling reaction

Supporting:

Wenjun Xie, Haoran Xiao, Xintong Wang, Zongze Huang, Xiling Bian, Kewei Wang, Qi Sun. Sonogashira coupling reaction in the synthesis of novel positive allosteric modulators of α7 nicotinic acetylcholine receptors[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(5): 374-381.

Figures/Tables 4

References 10

[1]	Elvevåg, B.; Goldberg, T.E. Cognitive impairment in schizophrenia is the core of the disorder. Crit. Rev. Neurobiol. 2000, 14, 1–21.
[2]	Ochoa, E.L.M.; Lasalde-Dominicci, J. Cognitive deficits in schizophrenia: focus on neuronal nicotinic acetylcholine receptors and smoking. Cell Mol. Neurobiol. 2007, 27, 609–639.
[3]	Stevens, K.E.; Freedman, R.; Collins, A.C.; Hall, M.; Leonard, S.; Marks, M.J.; Rose, G.M. Genetic correlation of inhibitory gating of hippocampal auditory evoked response and α-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains. Neuropsychopharmacology. 1996, 15, 152–162.
[4]	Felix, R.; Levin, E.D. Nicotinic antagonist administration into the ventral hippocampus and spatial working memory in rats. Neuroscience. 1997, 81, 1009–1017.
[5]	Corradi, J.; Bouzat, C. Understanding the bases of function and modulation of α7 nicotinic receptors: implications for drug discovery. Mol. Pharmacol. 2016, 90, 288–299.
[6]	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.; Wang, K.W.; Sun, Q. Design and synthesis of novel positive allosteric modulators of α7 nicotinic acetylcholine receptors with the ability to rescue auditory gating deficit in mice. J. Med. Chem. 2019, 62, 159–173.
[7]	Wang, X.; Xiao, H.; Wang, J.; Huang, Z.; Peng, G.; Xie, W.; Bian, X.; Liu, H.; Shi, C.; Yang, T.; Li, X.; Gao, J.; Meng, Y.; Jiang, Q.; Chen, W.; Hu, F.; Wei, N.; Wang, X.; Zhang, L.; Wang, K.; Sun, Q. Synthesis and biological evaluation of novel triazine derivatives as positive allosteric modulators of α7 nicotinic acetylcholine receptors. J. Med. Chem. 2021, 64, 12379–12396.
[8]	Tang, J.S.; Xie, B.X.; Bian, X.L.; Xue, Y.; Wei, N.N.; Zhou, J.H.; Hao, Y.C.; Li, G.; Zhang, L.R.; Wang, K.W. 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.
[9]	Wager, T.T.; Chandrasekaran, R.Y.; Hou, X.; Troutman, M.D.; Verhoest, P.R.; Villalobos, A.; Will, Y. Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes. ACS Chem. Neurosci. 2010, 1, 420–434.
[10]	daCosta, C.J.B.; Free, C.R.; Corradi, J.; Bouzat, C.; Sine, S.M. Single-channel and structural foundations of neuronal α7 acetylcholine receptor potentiation. J. Neurosci. 2011, 31, 13870–13879.

Sonogashira coupling reaction in the synthesis of novel positive allosteric modulators of α7 nicotinic acetylcholine receptors

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 4

References 10

Related Articles 2

Recommended Articles

Metrics

Comments

[1]	State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center. The research group of Professor Qi Sun has made new progress on α7 nAChR positive allosteric modulator and its improvement in cognitive dysfunction [J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(8): 701-702.
[2]	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.