Pentamidine analogs as inhibitors of [(3)H]MK-801 and [(3)H]ifenprodil binding to rat brain NMDA receptors.

Bioorganic & medicinal chemistry 2015 Aug 01

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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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Citation

Michael L Berger, Dorota Maciejewska, Jean Jacques Vanden Eynde, Madhusoodanan Mottamal, Jerzy Żabiński, Paweł Kaźmierczak, Mateusz Rezler, Ivana Jarak, Ivo Piantanida, Grace Karminski-Zamola, Annie Mayence, Patrick Rebernik, Arvind Kumar, Mohamed A Ismail, David W Boykin, Tien L Huang. Pentamidine analogs as inhibitors of [(3)H]MK-801 and [(3)H]ifenprodil binding to rat brain NMDA receptors. Bioorganic & medicinal chemistry. 2015 Aug 01;23(15):4489-4500