The research of our group is focused on GPCR-targeted medicinal chemistry and drug discovery. We leverage the knowledge on the structures and functions of G protein-coupled receptors (GPCRs) for the design of novel drug-like compounds with therapeutic potential. A major focus is targeting aminergic and orphan GPCRs for the design of next-generation therapeutics for the treatment of neuropsychiatric disorders, in particular, depression and schizophrenia.

From a medicinal chemistry perspective, our research goal is the design of novel drug-like compounds by addressing the following three scientific challenges in GPCR drug discovery: (1) Structure-based design of subtype-selective GPCR modulators; (2) Rational design of “biased” GPCR ligands that are functionally selective for a specific signaling pathway; (3) Rational design of GPCR ligands with desired polypharmacological profiles. Our research is dedicated to developing innovative therapeutics that address critical unmet needs in neuropsychiatric disorder treatment.

1. Wen YT^#,*, Tang LJ^#, Duan WW^#, Ren QF^#, Ni YY^#, Chen SY^#, Chen J^#, Yang L, Wang H, Chen Y, Zheng YZ, Pan XC, Du H, Huang MW, Zeng A, Zhou Z, Zhang ZG, Ji HB, Ge GX, Zeng Y A*, Zhang W*, Wang SH*, Cheng JJ*, Wang S*, Chen JF*. Targeting peripheral 5-HT2AR enhances antitumor immunity in colorectal cancer. Cell 2026, 189, 1-18.

2. Yan W^#,*, Feng M^#, Yang K, Yu C, Zhang W, Liu J, Xie C*, Cheng J*. Pharmacokinetics-Driven Optimization of Immunotherapeutic Agents Targeting the Adenosine A2A Receptor (A2AR) and Histone Deacetylases (HDACs). J Med Chem 2026, 69, 6038−6062.

3. Li R^#, Yan H^#, Chen Y, Liu Y, Tang L, Yu J, Liu J, Wang H, Wang S*, Cheng J*. Structure-Guided Design of Novel 5‑HT_2A Partial Agonists as Psychedelic Analogues with Antidepressant Effects. J Med Chem 2025, 68, 21683−21700.

4. Duan W, Cao D, Wang S*, Cheng J*. Serotonin 2A Receptor (5-HT_2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants. Chem Rev 2024, 124, 124-163.

5. Mao J^#, Cui Y^#, Wang H, Duan W, Liu Z-J, Hua T, Zhou N*, Cheng J*.  Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment. J Med Chem 2023, 66, 14011–14028.

6. Zhang J^#, Feng D^#, Cheng J*, Wuthrich K*. Adenosine A_2A Receptor (A_2AAR) Ligand Screening Using the ¹⁹F-NMR Probe FPPA. J Am Chem Soc 2023, 145, 15061−15064.

7. Liu R^#, Qi J^#, Wang H, Fan L, Zhang P, Yu J, Tan L, Wang S*, Cheng J*. Transformation of a Dopamine D₂ Receptor Agonist to Partial Agonists as Novel Antipsychotic Agents. J Med Chem 2023, 66, 6274−6287.

8. Sun N^#, Yang K^#, Yan W^#, Yao M, Yu C, Duan W, Gu X, Guo D, Jiang H, Xie C*, Cheng J*. Design and Synthesis of Triazole-Containing HDAC Inhibitors That Induce Antitumor Effects and Immune Response. J Med Chem 2023, 66, 4802−4826.

9. Gu X, Yuan H, Zhao W, Sun N, Yan W, Jiang C, He Y, Liu H, Cheng J*, Guo D*. Optical-Controlled Kinetic Switch: Fine-Tuning of the Residence Time of an Antagonist Binding to the Vasopressin V₂ Receptor in In Vitro, Ex Vivo, and In Vivo Models of ADPKD.J Med Chem 2023, 66, 1454−1466.

10. Wang J^#, Wu M^#, Chen Z^#, Wu L, Wang T, Cao D, Wang H, Liu S, Xu Y, Li F, Liu J, Chen N, Zhao S, Cheng J*, Wang S*, Hua T*. The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands. Nat Comm 2022, 13, 2855.

11. Zhang H^#, Yan W^#, Sun Y^#, Yuan H, Su L, Cao X, Wang P, Xu Z, Hu Y, Wang Z, Wang Y, Fu K, Sun Y, Chen Y*, Cheng J*, Guo, D*. Long Residence Time at the Vasopressin V₂ Receptor Translates into Superior Inhibitory Effects in ex vivo and in vivo Models of Autosomal Dominant Polycystic Kidney Disease. J Med Chem, 2022, 65, 7717−7728.

12. Cao D^#, Yu J^#, Wang H^#, Luo Z^#, Liu X^#, He L, Qi J, Fan L, Tang L, Chen Z, Li J, Cheng J*, Wang S*. Structure-based discovery of non-hallucinogenic psychedelic analogs. Science 2022, 375, 403-411.

13. Chen Z^#, Fan L^#, Wang H^#, Yu J^#, Lu D^#, Qi J, Nie F, Luo Z, Liu Z, Cheng J*, Wang S*. Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties. Nat Neurosci 2022, 25, 39–49.

14. Yan W^#, Fan L^#, Yu J, Liu R, Wang H, Tan L, Wang S*, Cheng J*. 2-Phenylcyclopropyl-methylamine (PCPMA) derivatives as dopamine D₂ receptor partial agonists: Design, synthesis and biological evaluation.J Med Chem 2021, 64, 17239-17258.

15. Yan W^#, Ling L^#, Wu Y, Yang K, Liu R, Zhang J, Zhao S, Zhong G, Zhao S, Jiang H*, Xie C*, Cheng J*. Structure-based design of dual-acting compounds targeting adenosine A_2A receptor and histone deacetylase as novel tumor immunotherapeutic agents. J Med Chem 2021, 64, 16573-16597.

16. Duan W^#, Sun Y^#, Wu M^#, Zhang Z, Zhang T, Wang H, Li F, Yang L, Xu Y, Liu Z-J, Hua T*, Nie H*, Cheng J*. Carbon-silicon switch led to the discovery of novel synthetic cannabinoids with therapeutic effects in a mouse model of multiple sclerosis. Eur J Med Chem 2021, 226, 113878.

17. Zhang J, Yan W, Duan W, Wüthrich K, Cheng J*. Tumor Immunotherapy Using A2A Adenosine Receptor Antagonists. Pharmaceuticals 2020, 13, 237.

18. Fan L^#, Tan L^#, Chen Z, Qi J, Nie F, Luo Z,Cheng J*, Wang S*. Haloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands. Nat Commun 2020, 11, 1074.

19. Chan HCS^#, Xu Y^#, Tan L^#, Vogel H, Cheng J*, Wu D*, Yuan S*. Enhancing the Signaling of GPCRs via Orthosteric Ions, ACS Cent Sci 2020, 6, 274−282.

20. Tan L#, Zhou Q#, Yan W, Sun J, Kozikowski AP, Zhao S, Huang X-P*, Cheng J*. Design and Synthesis of Bitopic 2 Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands. J Med Chem 2020, 63, 4579-4602.