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Replacement of benzylpiperidine moiety by fluorinated phenylalkyl side chains for the development of novel GluN2B receptor ligands.
ChemMedChem 2018 October 13
The 4-benzylpiperidine moiety represents a central structural element of potent N-methyl-D-aspartate (NMDA) receptor antagonists containing the GluN2B subunit. In order to obtain novel GluN2B ligands suitable for positron emission tomography the benzylpiperidine moiety was replaced by fluorinated ω-phenylalkylamino groups. For this purpose three primary propyl- and butylamines 7a-c and one butyraldehyde 7d bearing a fluorine atom and an ω-phenyl moiety were prepared in 3-7 step syntheses. 7a d were attached to various scaffolds of potent GluN2B antagonists (scaffold hopping) instead of the original 4-benzylpiperidine moiety. Although benzoxazol-2-ones (3,4) and indoles (5) with benzylpiperidine moiety show high GluN2B affinity, the corresponding fluorophenylalkylamine derivatives 8 - 11 did not result in high Glu2B affinity. Moderate GluN2B affinity was observed for 3-(fluoroalkyl) substituted tetrahydro-1H-3 benzazepine 13a (Ki = 239 nM). However, high GluN2B affinity was obtained for the tetrahydro-5H-benzo[7]annulen-7-amines 12a-c (Ki = 17-30 nM). Docking studies resulted in the same binding pose for 12a as fior the lead compound Ro 25.6981 (2). It can be concluded that some GluN2B ligands (benzoxazolones, indoles) do not tolerate replacement of the 4-benzylpiperidine moiety by flexible fluorinated phenylalkyl side chains, but other scaffolds such as tetrahydro-3-benzazepines and -benzo[7]annulenes (6) retain interaction with NMDA receptors containing the GluN2B subunit.
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