title: Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction.
abstract: The protein--protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treating ischemic brain diseases, neuropathic pain, and Alzheimer's disease. We have previously demonstrated that N-alkylated tetrapeptides are potent inhibitors of this interaction, and here, this template is exploited for the development of blood plasma-stable and cell-permeable inhibitors. Initially, we explored both the amino acid sequence of the tetrapeptide and the nature of the N-alkyl groups, which consolidated N-cyclohexylethyl-ETAV (1) as the most potent and selective compound. Next, the amide moieties of N-methylated ETAV were systematically replaced with thioamides, demonstrating that one of three amide bonds could be replaced without compromising the affinity. Subsequent optimization of the N-alkyl groups and evaluation of cell permeability led to identification of N-cyclohexylethyl-ETA(S)V (54) as the most potent, plasma-stable and cell-permeable inhibitor, which is a promising tool in unraveling the therapeutic potential of the PSD-95/NMDA receptor interaction.
authors.affiliation: Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Bach
authors.forename: Jonas N N
authors.initials: JN
authors.lastname: Eildal
authors.forename: Nicolai
authors.initials: N
authors.lastname: Stuhr-Hansen
authors.forename: Rasmus
authors.initials: R
authors.lastname: Deeskamp
authors.forename: Marie
authors.initials: M
authors.lastname: Gottschalk
authors.forename: Søren W
authors.initials: SW
authors.lastname: Pedersen
authors.forename: Anders S
authors.initials: AS
authors.lastname: Kristensen
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: D000818:Animals; D019556:COS Cells; D002463:Cell Membrane Permeability; D002522:Chlorocebus aethiops; D000076122:Disks Large Homolog 4 Protein; D004355:Drug Stability; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054731:PDZ Domains; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009842:Oligopeptides; D057786:Peptidomimetics; D016194:Receptors, N-Methyl-D-Aspartate