Gq-biased CCKBR agonist

Improves AD cognition

A synthetic CCKBR agonist that selectively activates Gq signaling, improving cognition and reducing amyloid plaques in Alzheimer's disease mouse models.

Wang, Le · Sha Xue, · Zi-Dong, Zhang · Wei-Ming, Huang · Lin, Hui · Zhang, Nan · Xia, Xin · Yu-Nan, Sun · Ding, Hui · Zhao, Rui · Cheng, Jie · Shang, Pan · Wang, Peng · Liu, Jun · Yang, Fan · Xiao, Peng · Wang, Wen · Zhao, Dong · Tang, Yi · Tie, Lu · Du, Yang · Zhang, Yong · He, Jufang · Sun, Jinpeng

Cell 2025

Advantages

Selective Gq activation

Structural insights enable rational design of Gq-biased agonist 3r1, avoiding Gi activation and potentially reducing side effects.

Improves cognition

3r1 significantly ameliorates cognitive decline in the 5×FAD mouse model.

Reduces Aβ plaques

3r1 reduces the number of amyloid-β plaques in 5×FAD mice.

Enhances synaptic plasticity

Promotes long-term potentiation (LTP) via upregulation of ADAM10 and PLCB4, key mechanisms for learning and memory.

Applications

• Alzheimer's disease therapy：As a Gq-biased agonist, it directly targets disease-relevant signaling, offering a novel therapeutic approach.
• Neurodegenerative disorders：By improving cognition and synaptic function, it may be applicable to various neurodegenerative conditions.
• GPCR agonists：Provides a structural template and design paradigm for developing selective GPCR agonists.