Premium
Replacement of the Benzylpiperidine Moiety with Fluorinated Phenylalkyl Side Chains for the Development of GluN2B Receptor Ligands
Author(s) -
Thum Simone,
Schepmann Dirk,
Kalinin Dmitrii V.,
Ametamey Simon M.,
Wünsch Bernhard
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800566
Subject(s) - moiety , chemistry , stereochemistry , quinoxaline , nmda receptor , combinatorial chemistry , receptor , organic chemistry , biochemistry
The 4‐benzylpiperidine moiety is a central structural element of potent N ‐methyl‐ d ‐aspartate (NMDA) receptor antagonists containing the GluN2B subunit. To obtain novel GluN2B ligands suitable for positron emission tomography, the benzylpiperidine moiety was replaced with fluorinated ω‐phenylalkylamino groups. For this purpose three primary propyl‐ and butylamines 7 a – c and one butyraldehyde 7 d bearing a fluorine atom and an ω‐phenyl moiety were prepared in 3‐ to 7‐step syntheses. Compounds 7 a – d were attached to various scaffolds of potent GluN2B antagonists (scaffold hopping) instead of the original 4‐benzylpiperidine moiety. Although benzoxazol‐2‐ones and indoles with a benzylpiperidine moiety show high GluN2B affinity, the corresponding fluorophenylalkylamine derivatives did not result in high Glu2B affinity. Moderate GluN2B affinity was observed for a 3‐(fluoroalkyl)‐substituted tetrahydro‐1 H ‐3‐benzazepine ( K i =239 n m ). However, high GluN2B affinity was obtained for the tetrahydro‐5 H ‐benzo[7]annulen‐7‐amines 12 a – c ( K i =17–30 n m ). Docking studies resulted in the same binding pose for 12 a as for the lead compound Ro 25‐6981. It can be concluded that some GluN2B ligands (benzoxazolones, indoles) do not tolerate replacement of the 4‐benzylpiperidine moiety with flexible fluorinated phenylalkyl side chains, but other scaffolds such as tetrahydro‐3‐benzazepines and ‐benzo[7]annulenes retain interaction with NMDA receptors containing the GluN2B subunit.