研究方向：靶向G蛋白偶联受体（GPCR）的药物发现

1. 靶向单胺类GPCR的抗精神疾病药物发现

精神类疾病如精神分裂症、抑郁症与多巴胺受体、血清素受体、M型乙酰胆碱受体等单胺类GPCR的功能异常相关。我们以单胺类GPCR为靶标，以“受体-配体”复合物结构为指导，设计合成具有受体亚型高选择性或信号通路“偏向性”的新型小分子化合物，并进行相应的药理药效研究，以获得具有更优药效、更少毒副作用的新型抗精神疾病候选药物。

2. 靶向腺苷信号通路的抗肿瘤药物发现

肿瘤微环境中，腺苷是重要的免疫抑制因子。腺苷通过激活腺苷受体发挥免疫抑制作用，而腺苷受体拮抗剂能够拮抗腺苷的免疫抑制作用发挥抗肿瘤活性。我们以腺苷受体为靶标，进行具有新机制的小分子药物的设计合成，并研究其抗肿瘤活性，以获得新型抗肿瘤候选药物。

• 基于致幻剂机制的偏向性5-HT2A受体激动剂设计与抗抑郁活性研究（Science 2022；Chem Rev 2024）

• 多巴胺D2受体部分激动剂设计与新型抗精神分裂症药物发现（Nat Neurosci 2022；J Med Chem 2021；J Med Chem 2023）

• 基于柔性可变骨架的多靶标多功能GPCR药物设计（Cell 2024）

• 具有抗精神分裂症活性的新型GPR139激动剂发现（J Med Chem 2023）

• 基于PCPMA优势骨架的药物设计（J Med Chem 2020；J Med Chem 2021）

• 腺苷A2a受体拮抗/HDAC活性抑制的双功能抗肿瘤化合物（J Med Chem 2021；J Med Chem 2023）

• Chen Z#, Yu J#, Wang H#, Xu P#, Fan L, Sun F, Huang S, Zhang P, Huang H, Gu S, Zhang B, Zhou Y, Wan X, Pei G, Xu H.E*, Cheng J*, Wang S*. Flexible scaffold-based cheminformatics approach for polypharmacological drug design. Cell 2024, 187, 2194-2208.

• 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.

• Li H, Cheng J*. 2-Phenylcyclopropylmethylamine (PCPMA) as a privileged scaffold for central nervous system drug design. Bioorg Med Chem Lett 2024, 101, 129654.

• Liu R, Duan W, Yan W, Zhang J, Cheng J*. Design and synthesis of tri-substituted pyrimidine derivatives as bifunctional tumor immunotherapeutic agents targeting both A_2A adenosine receptors and histone deacetylases. Chin Chem Lett 2024, 35, 108136.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• Zhang J^#, Luo Z^#, Duan W, Yang K, Ling L, Yan W, Liu R, Wüthrich K, Jiang H*, Xie C*, Cheng J*. Dual-acting antitumor agents targeting the A_2A adenosine receptor and histone deacetylases: Design and synthesis of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives. Eur J Med Chem, 2022, 236, 114326.

• 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.

• 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.

• 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.

• 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.

• 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.

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

• 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.

• 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.

• 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.