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

A new series of fluorinated 5-HT 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-HT receptors reveals high potency for compounds (+)-21a-d. In particular, (+)-21b had no detectable 5-HT agonism and displayed reasonable selectivity against 5-HT. Molecular docking studies were further performed to explain the compounds' possible binding poses to the 5-HT receptor.