title: Pentamidine analogs as inhibitors of [(3)H]MK-801 and [(3)H]ifenprodil binding to rat brain NMDA receptors.
abstract: The anti-protozoal drug pentamidine is active against opportunistic Pneumocystis pneumonia, but in addition has several other biological targets, including the NMDA receptor (NR). Here we describe the inhibitory potencies of 76 pentamidine analogs at 2 binding sites of the NR, the channel binding site labeled with [(3)H]MK-801 and the [(3)H]ifenprodil binding site. Most analogs acted weaker at the ifenprodil than at the channel site. The spermine-sensitivity of NR inhibition by the majority of the compounds was reminiscent of other long-chain dicationic NR blockers. The potency of the parent compound as NR blocker was increased by modifying the heteroatoms in the bridge connecting the 2 benzamidine moieties and also by integrating the bridge into a seven-membered ring. Docking of the 45 most spermine-sensitive bisbenzamidines to a recently described acidic interface between the N-terminal domains of GluN1 and GluN2B mediating polyamine stimulation of the NR revealed the domain contributed by GluN1 as the most relevant target.
authors.affiliation: Center for Brain Research, Medical University of Vienna, Vienna, Austria. Electronic address: michael.berger@meduniwien.ac.at.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Berger
authors.affiliation: Department of Organic Chemistry, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Maciejewska
authors.affiliation: Laboratory of Organic Chemistry, University of Mons-UMONS, Mons, Belgium.
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Vanden Eynde
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, New Orleans, USA.
authors.forename: Madhusoodanan
authors.initials: M
authors.lastname: Mottamal
authors.affiliation: Department of Organic Chemistry, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Żabiński
authors.affiliation: Department of Organic Chemistry, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Kaźmierczak
authors.affiliation: Department of Organic Chemistry, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Rezler
authors.affiliation: Department of Organic Chemistry, University of Zagreb, Zagreb, Croatia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Jarak
authors.affiliation: Department of Organic Chemistry, University of Zagreb, Zagreb, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Piantanida
authors.affiliation: Department of Organic Chemistry, University of Zagreb, Zagreb, Croatia.
authors.forename: Grace
authors.initials: G
authors.lastname: Karminski-Zamola
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, New Orleans, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Mayence
authors.affiliation: Center for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Rebernik
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ismail
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, New Orleans, USA.
authors.forename: Tien L
authors.initials: TL
authors.lastname: Huang
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism; D014316:Tritium / Q000737:chemistry
chemical_list: D010879:Piperazines; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D000077489:Piperazine; D010419:Pentamidine; D016291:Dizocilpine Maleate; C010739:ifenprodil
keywords: Alkylation; Bisbenzamidine; Coupling; Ifenprodil; Molecular docking; NMDA receptor; Pentamidine; Polyamine; Radioligand binding; Rat brain