Synthesis, GluN2B Affinity and Selectivity of benzo[7]annulen-7-amines

Bioorg Med Chem. 2014 Dec 1;22(23):6638-6646. doi: 10.1016/j.bmc.2014.10.004. Epub 2014 Oct 12.

Abstract

Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)3 led to the secondary amines 6a-d, cis-6h and trans-6i. The tertiary amines 6e-g were obtained by SN2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (Ki=2.3nM and 2.9nM, respectively). With respect to selectivity against the PCP binding site, σ1 and σ2 receptors the phenylpiperazine 6f is the most promising GluN2B antagonist.

Keywords: Benzo[7]annulen-7-amines; Conformational restriction; GluN2B antagonists; NMDA receptor; Selectivity; Structure affinity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzocycloheptenes / chemical synthesis*
  • Benzocycloheptenes / chemistry
  • Benzocycloheptenes / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Structure-Activity Relationship

Substances

  • 1-phenyl-4-(6,7,8,9-tetrahydro-5H-benzo(7)annulen-7-yl)piperazine
  • Benzocycloheptenes
  • NR2B NMDA receptor
  • Piperazines
  • Receptors, N-Methyl-D-Aspartate