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

被引：13

作者：

Berger, Michael L. ^{[1
]}

Maciejewska, Dorota ^{[2
]}

Vanden Eynde, Jean Jacques ^{[3
]}

Mottamal, Madhusoodanan ^{[4
]}

Zabinski, Jerzy ^{[2
]}

Kazmierczak, Pawel ^{[2
]}

Rezler, Mateusz ^{[2
]}

Jarak, Ivana ^{[5
]}

Piantanida, Ivo ^{[5
]}

Karminski-Zamola, Grace ^{[5
]}

Mayence, Annie ^{[4
]}

Rebernik, Patrick ^{[1
]}

Kumar, Arvind ^{[6
]}

Ismail, Mohamed A. ^{[6
]}

Boykin, David W. ^{[6
]}

Huang, Tien L. ^{[4
]}

机构：

[1] Med Univ Vienna, Ctr Brain Res, Vienna, Austria

[2] Med Univ Warsaw, Dept Organ Chem, Warsaw, Poland

[3] Univ Mons, Organ Chem Lab, B-7000 Mons, Belgium

[4] Xavier Univ Louisiana, Coll Pharm, New Orleans, LA USA

[5] Univ Zagreb, Dept Organ Chem, Zagreb 41000, Croatia

[6] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 15期

关键词：

Pentamidine; NMDA receptor; Ifenprodil; Polyamine; Bisbenzamidine; Alkylation; Coupling; Radioligand binding; Rat brain; Molecular docking; PNEUMOCYSTIS-CARINII AGENTS; QUINOLINIC ACID; SOLID-STATE; 1,5-BIS(4-AMIDINOPHENOXY)PENTANE PENTAMIDINE; SUBUNIT ARRANGEMENT; STRUCTURAL-ANALYSIS; NMR-SPECTROSCOPY; MOLECULAR-BASIS; POLYAMINES; IFENPRODIL;

D O I：

10.1016/j.bmc.2015.06.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 [H-3]MK-801 and the [H-3]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. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：4489 / 4500

页数：12

共 56 条

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