Do GluN2B subunit containing NMDA receptors tolerate a fluorine atom in the phenylalkyl side chain?

Abstract

The influence of an F-atom in the side chain of benzo[7]annulen-7-amines on the affinity towards GluN2B subunit containing NMDA receptors and the selectivity over related receptors was investigated. The synthesis of and was performed by reductive amination of the ketone with primary alkanamines and bearing an F-atom in β-position. The GluN2B affinities of non-fluorinated and fluorinated ligands and are almost identical. The low impact of the F-atom on GluN2B affinity was unexpected, as it influences several chemical and physicochemical properties of the ligands. However, introduction of the F-atom led to reduced selectivity over receptors. Whereas and display still a 2-3-fold preference for GluN2B over receptors, they show almost the same affinity to GluN2B and receptors.

Replacement of the Benzylpiperidine Moiety with Fluorinated Phenylalkyl Side Chains for the Development of GluN2B Receptor Ligands

“…In contrast, 3‐benzazepine 13 a bearing the 2‐fluoro‐4‐phenylbutyl substituent at the nitrogen atom shows moderate GluN2B affinity with a K i value of 239 n m . The high GluN2B affinity of benzo[7]annulen‐7‐amines 12 a and 12 b with fluorinated phenylalkyl side chains at the exocyclic amino moiety was already reported . The novel analogue 12 c , which represents a regioisomer of 12 b , completes this set of ligands.…”

“…According to the established procedure for the synthesis of the β‐fluorinated 4‐phenylbutylamine 7 b , 3‐phenylpropan‐1‐amine 7 a fluorinated in 2‐position was synthesized in an analogous manner (Scheme ). This method is superior to the longer route via opening of an oxirane .…”

“…According to the established procedure for the synthesis of the β‐fluorinated 4‐phenylbutylamine 7 b , 3‐phenylpropan‐1‐amine 7 a fluorinated in 2‐position was synthesized in an analogous manner (Scheme ). This method is superior to the longer route via opening of an oxirane . The bromofluoro intermediates 23 a and 23 b were obtained by reaction of the terminal olefins 22 a and 22 b with N ‐bromosuccinimide (NBS) and Et 3 N⋅3 HF.…”

“… Synthesis of benzo[7]annulene‐7‐amines 12 a – c : (a) NaBH(OAc) 3 , CH 2 Cl 2 , RT, 5–24 h, 50 % ( 12 a ), 34 % ( 12 b ), 79 % ( 12 c ).…”

“…This decreased GluN2B affinity of the benzoxazolones 8 and 9 and indoles 10 and 11 is rather surprising and difficult to explain. In a previous study we have shown that introduction of a fluorine atom into phenylalkyl side chains was well tolerated . To analyze, whether the additional fluorine atom or the increased flexibility of the phenylalkyl side chain is responsible for the loss of aGluN2B affinity, the non‐fluorinated benzoxazolones 9 e and 9 f were included into this study.…”