2. Academic Validation
  3. Design of fluorinated cyclopropane derivatives of 2-phenylcyclopropylmethylamine leading to identification of a selective serotonin 2C (5-HT2C) receptor agonist without 5-HT2B agonism

Design of fluorinated cyclopropane derivatives of 2-phenylcyclopropylmethylamine leading to identification of a selective serotonin 2C (5-HT2C) receptor agonist without 5-HT2B agonism

  • Eur J Med Chem. 2019 Nov 15:182:111626. doi: 10.1016/j.ejmech.2019.111626.
Guiping Zhang 1,  John D McCorvy 2,  Sida Shen 3,  Jianjun Cheng 4,  Bryan L Roth 2,  Alan P Kozikowski 5
Affiliations

Affiliations

  • 1 Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, United States. Electronic address: guipingz@starwisetrx.com.
  • 2 National Institute of Mental Health Psychoactive Drug Screening Program, and Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, 27599, United States.
  • 3 Departments of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, and Center for Developmental Therapeutics, Northwestern University, Evanston, IL, 60208, United States.
  • 4 iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • 5 Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, United States.
PMID: 31445232 DOI: 10.1016/j.ejmech.2019.111626
Abstract

A new series of fluorinated 5-HT2C agonists were designed and synthesized on the basis of our previous work on 2-phenylcyclopropylmethylamines as a potential approach for the treatment of central nervous system disorders. Key fluorinated cyclopropane moieties were constructed through transition metal catalyzed [2 + 1]-cycloaddition of aromatic vinyl fluorides, and the absolute stereochemistry of the representative compound (-)-21a was established. Functional activity measuring calcium flux at 5-HT2 receptors reveals high potency for compounds (+)-21a-d. In particular, (+)-21b had no detectable 5-HT2B agonism and displayed reasonable selectivity against 5-HT2A. Molecular docking studies were further performed to explain the compounds' possible binding poses to the 5-HT2C receptor.

Keywords

5-HT(2B) receptor; 5-HT(2C) receptor; Agonist; Asymmetric synthesis; Fluorinated cyclopropane.

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