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

Guiping Zhang; John D McCorvy; Sida Shen; Jianjun Cheng; Bryan L Roth; Alan P Kozikowski

doi:10.1016/j.ejmech.2019.111626

Design of fluorinated cyclopropane derivatives of 2-phenylcyclopropylmethylamine leading to identification of a selective serotonin 2C (5-HT_2C) receptor agonist without 5-HT_2B agonism

Eur J Med Chem. 2019 Nov 15:182:111626. doi: 10.1016/j.ejmech.2019.111626. Epub 2019 Aug 14.

Authors

Guiping Zhang¹, John D McCorvy², Sida Shen³, Jianjun Cheng⁴, Bryan L Roth², Alan P Kozikowski⁵

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.

Abstract

A new series of fluorinated 5-HT_2C 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-HT_2B agonism and displayed reasonable selectivity against 5-HT_2A. Molecular docking studies were further performed to explain the compounds' possible binding poses to the 5-HT_2C receptor.

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

Published by Elsevier Masson SAS.

MeSH terms

Cyclopropanes / chemical synthesis
Cyclopropanes / chemistry
Cyclopropanes / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Halogenation
Humans
Methylamines / chemical synthesis
Methylamines / chemistry
Methylamines / pharmacology*
Molecular Docking Simulation
Molecular Structure
Receptor, Serotonin, 5-HT2B / metabolism
Receptor, Serotonin, 5-HT2C / metabolism*
Structure-Activity Relationship

Substances

Cyclopropanes
Methylamines
Receptor, Serotonin, 5-HT2B
Receptor, Serotonin, 5-HT2C
cyclopropane

Grants and funding

R01 MH099993/MH/NIMH NIH HHS/United States