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  3. Design, synthesis, and pharmacological evaluation of novel M4 muscarinic receptor positive allosteric modulators for schizophrenia treatment

Design, synthesis, and pharmacological evaluation of novel M4 muscarinic receptor positive allosteric modulators for schizophrenia treatment

  • Eur J Med Chem. 2025 Nov 15:298:117993. doi: 10.1016/j.ejmech.2025.117993.
Yi Luo 1,  Yinli Qiu 2,  Ying Lin 1,  Quxiang Li 3,  Lingsheng Fu 1,  Xiangqing Xu 3,  Yiwen Shi 1,  Tao Lu 4,  Xian Wei 5,  Xiangyang Xu 6,  Yadong Chen 7,  Yu Jiao 8
Affiliations

Affiliations

  • 1 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 2 Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd & Jiangsu Key Laboratory of Central Nervous System Drug Research and Development, Xuzhou, 221116, PR China. Electronic address: qiuyinli@nhwa-group.com.
  • 3 Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd & Jiangsu Key Laboratory of Central Nervous System Drug Research and Development, Xuzhou, 221116, PR China.
  • 4 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 5 Department of Pharmacy, Youjiang Medical University for Nationalities, 98 ChengXiang Road, Baise, 533000, PR China. Electronic address: wei700@126.com.
  • 6 Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd & Jiangsu Key Laboratory of Central Nervous System Drug Research and Development, Xuzhou, 221116, PR China. Electronic address: xuxiangyang@nhwa-group.com.
  • 7 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: ydchen@cpu.edu.cn.
  • 8 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: jiaoyu@cpu.edu.cn.
PMID: 40752341 DOI: 10.1016/j.ejmech.2025.117993
Abstract

The muscarinic acetylcholine M4 receptor (M4 mAChR) has emerged as a promising target for schizophrenia treatment. M4 positive allosteric modulators (PAMs) can enhance endogenous acetylcholine signaling by binding to the allosteric site of the receptor. Compared with M4 agonists, the regulation of M4 mAChR function by PAMs is more precise and has fewer off-target effects. M4 PAMs under research have demonstrated excellent subtype selectivity and favorable safety profiles, but their efficacy has been limited in clinical trials. To improve the therapeutic efficacy, a series of novel M4 PAMs containing a biphenyl scaffold were designed and synthesized based on the existing M4 PAM structures. Among them, compound A9 (EC50 = 513 nM) demonstrated promising M4 mAChR selectivity, PAM activity, and favorable pharmacokinetic properties. Moreover, in the mice hyperactivity model, A9 reversed MK-801-induced hyperlocomotion (ED50 = 20.04 mg/kg, p.o.). These findings provide a scientific basis for the rational design of novel M4 PAMs with optimized pharmacological profiles and enhanced therapeutic potential for better schizophrenia treatment.

Keywords

Muscarinic acetylcholine receptor subtype 4; Schizophrenia; Selective M(4) positive allosteric modulators.

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