Novel substituted 4-(Arylethynyl)-Pyrrolo[2,3-d]pyrimidines negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu5) Treat depressive disorder in mice

Yonglei Du; Feng Gao; Hongwei Sun; Chenglin Wu; Guoqi Zhu; Manzhou Zhu

doi:10.1016/j.ejmech.2023.115855

Novel substituted 4-(Arylethynyl)-Pyrrolo[2,3-d]pyrimidines negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu5) Treat depressive disorder in mice

Eur J Med Chem. 2023 Dec 5:261:115855. doi: 10.1016/j.ejmech.2023.115855. Epub 2023 Oct 11.

Authors

Yonglei Du¹, Feng Gao², Hongwei Sun¹, Chenglin Wu³, Guoqi Zhu⁴, Manzhou Zhu⁵

Affiliations

¹ Department of Chemistry and Centre for Atomic Engineering of Advanced Materials, Key Laboratory of Structure and Functional Regulation of Hybrid Materials of Ministry of Education, Institutes of Physical Science and Information Technology and Anhui Province Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials, Anhui University, Hefei, Anhui, 230601, China.
² Key Laboratory of Xin'an Medicine, the Ministry of Education and Key Laboratory of Molecular Biology (Brain diseases), Anhui University of Chinese Medicine, Hefei, 230012, China.
³ School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China. Electronic address: 2200021@sumhs.edu.cn.
⁴ Key Laboratory of Xin'an Medicine, the Ministry of Education and Key Laboratory of Molecular Biology (Brain diseases), Anhui University of Chinese Medicine, Hefei, 230012, China. Electronic address: guoqizhu@gmail.com.
⁵ Department of Chemistry and Centre for Atomic Engineering of Advanced Materials, Key Laboratory of Structure and Functional Regulation of Hybrid Materials of Ministry of Education, Institutes of Physical Science and Information Technology and Anhui Province Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials, Anhui University, Hefei, Anhui, 230601, China. Electronic address: zmz@ahu.edu.cn.

PMID: 37847955
DOI: 10.1016/j.ejmech.2023.115855

Abstract

In view of the fact that the G-protein-coupled receptors (GPCRs) sit at the top of the signaling pathways triggering a diverse range of signaling cascades towards a cellular event, GPCRs are regarded as central drug targets. mGlu5, a type of classical GPCRs, is highly expressed in the central nervous system (CNS) and responds to the neurotransmitter glutamate. Researches show that mGlu5 is a potential drug target for the treatment of depression. Up to now, multiple mGlu5 negative allosteric modulators (NAMs) have entered clinical trials, but no small molecule mGlu5 NAM has yet to reach market. Herein, we report the structural optimization and structure-activity relationship studies of a series of novel mGlu5 NAMs. Among them, the novel compound 10b is a high-affinity mGluR5 antagonist, with an IC₅₀ value of 11.5 nM. Besides, we evaluated the anti-depressant effect of compound 10b using the chronic unpredictable mild stress (CUMS)-induced depression model. The data showed that the mice in CUMS group were featured by decreased level of serum 5-HT and increased level of serum CORT, and the expression of synaptic proteins were reduced, including GluA1, GluA2, p-PKA, BDNF and TrkB. However, those factors for identifying sensitivity to depression-like behaviors could be improved by compound 10b treatment. The preliminary toxicology evaluations indicated that compound 10b had a good safety profile in vivo. Collectively, the compound 10b represents a promising lead compound for the treatment of depressive disorder.

Keywords: CUMS; Depression; GPCRs; Substituted 4-(arylethynyl)-pyrrolo[2,3-d]pyrimidines; mGluR5 NAMs.

MeSH terms

Allosteric Regulation
Animals
Central Nervous System
Depressive Disorder*
Mice
Pyrimidines* / chemistry
Pyrimidines* / pharmacology
Receptors, G-Protein-Coupled
Structure-Activity Relationship

Substances

Pyrimidines
Receptors, G-Protein-Coupled