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
Date
08/25/2019Pubmed ID
31445232Pubmed Central ID
PMC6815260DOI
10.1016/j.ejmech.2019.111626Scopus ID
2-s2.0-85070920510 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
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.
Author List
Zhang G, McCorvy JD, Shen S, Cheng J, Roth BL, Kozikowski APAuthor
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
CyclopropanesDose-Response Relationship, Drug
Drug Design
Halogenation
Humans
Methylamines
Molecular Docking Simulation
Molecular Structure
Receptor, Serotonin, 5-HT2B
Receptor, Serotonin, 5-HT2C
Structure-Activity Relationship
