2. Academic Validation
  3. Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN

Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN

  • Science. 2022 Oct 28;378(6618):390-398. doi: 10.1126/science.abo3566.
Nan Sun # 1 2,  Ya-Juan Qin # 3,  Chu Xu # 1 4,  Tian Xia # 1,  Zi-Wei Du 1,  Li-Ping Zheng 3,  An-An Li 5,  Fan Meng 1,  Yu Zhang 1,  Jing Zhang 1,  Xiao Liu 6,  Ting-You Li 3,  Dong-Ya Zhu 1 7,  Qi-Gang Zhou 1 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Reproductive Medicine, Department of Clinic Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 2 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou 221004, China.
  • 3 Department of Pharmacochemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 4 Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing 210042, China.
  • 5 Jiangsu Key Laboratory of Brain Disease and Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xu Zhou 221004, China.
  • 6 College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 7 The Key Center of Gene Technology Drugs of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China.
  • 8 Department of Clinic Pharmacology, Sir runrun Hospital, Nanjing Medical University, Nanjing 211167, China.
  • # Contributed equally.
PMID: 36302033 DOI: 10.1126/science.abo3566
Abstract

Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the Serotonin Transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.

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