Pentamidine analogs as inhibitors of [3H]MK-801 and [3H]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 [3H]MK-801 and the [3H]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.

Synthesis, radiolabeling and evaluation of novel amine guanidine derivatives as potential positron emission tomography tracers for the ion channel of the N-methyl-d-aspartate receptor

“…The residue was purified by column chromatography over silica with dichloromethane to obtain the title compound as a light brown solid ( 4.2.11. N-(3-(2,5-Dimethyl-1H-pyrrol-1-yl)phenyl)cyanamide (11) To a stirred mixture of 3-(2,5-dimethyl-1H-pyrrol-1-yl)aniline (10) (3.88 g, 20.8 mmol) and anhydrous sodium acetate (5.19 g, 63.3 mmol) in methanol (35 mL) at 0 was added a solution of cyanogen bromide [CAUTION highly toxic] (2.88 g, 27.2 mmol) in methanol (35 mL) via an addition funnel. After 2 h of stirring the ice-bath was removed and stirring was continued for 24 h. The reaction mixture was diluted with dichloromethane (150 mL) and washed with 1 M HCl (150 mL).…”

“…To study the metabolic profile of [ 11 26 in the tail vein without anesthesia. After 15 or 45 min the rats were decapitated.…”

“…The biodistribution of [ 11 26 in the tail vein without anesthesia and were decapitated at either 5, 15, 30 or 60 min after injection. Blood, heart, lung, liver, kidney and bone were removed.…”

“…-5-(methylthio)phenyl)-1-methyl-1-(3-([11 C] methylamino)phenyl)guanidine ([ 11 C]23) [ 11 C]23 was synthesized accordingly to [ 11 C]21. Eluent preparative HPLC 10 mM ammonium hydrogen carbonate pH ¼ 7.4/ acetonitrile 35/65 v/v, retention time 7 min.…”

Mechanisms of NMDA receptor inhibition by diarylamidine compounds

“…In contrast, Williams and coauthors demonstrated serious voltage dependence in experiments with NR1/NR2B receptors expressed in Xenopus oocytes (Williams, Dattilo, Sabado, Kashiwagi, & Igarashi, ). Many derivatives of pentamidine also inhibit NMDA receptors (Berger et al, ; Reynolds et al, ; Tao, Huang, Sharma, Reynolds, & Donkor, ). They can displace both [(3)H]MK‐801 and the [(3)H]ifenprodil binding.…”