Synthesis of N,N'-Substituted Piperazine and Homopiperazine Derivatives with Polyamine-like Actions at N-Methyl-D-aspartate Receptors

Abstract

A series of N,N'-substituted piperazine and homopiperazine derivatives have been synthesized with the objective of producing compounds that interact with polyamine modulatory sites on N-methyl-D-aspartate (NMDA) receptors. These novel compounds exhibited polyamine-like actions, enhancing [3H]MK-801 binding to NMDA receptors in rat forebrain membranes. The potencies of N,N'-bis(2-aminoacetyl)homopiperazine (15), N,N'-bis(N-methyl-4-aminobutyl)-piperazine (7), and N,N'-bis(3-aminopropyl)homopiperazine (11) (EC50 18.0, 21.3, and 24.4 microM, respectively) to enhance [3H]MK-801 binding were comparable to that of spermine (EC50 5.2 microM). However, the efficacies of 15, 7, and 11 in this measure were lower (by approximately 40%, 32%, and 24%, respectively) than spermine, which may be indicative of partial agonist actions. Like spermine, the ability of these piperazine and homopiperazine derivatives to enhance [3H]MK-801 binding could be inhibited by both a competitive polyamine antagonist (arcaine) and a specific, noncompetitive polyamine antagonist (conantokin-G). However, unlike endogenous polyamines, high concentrations (up to 1 mM) of these novel polyamine-like compounds did not inhibit [3H]MK-801 binding. N,N'-Aminoalkylated and aminoacylated piperazine and homopiperazine derivatives may prove useful for studying polyamine recognition sites associated with NMDA receptors.

Molecular Features Associated with Polyamine Modulation of NMDA Receptors

“…Pharmacology. The regulatory effects of the diamines examined in this study were evaluated using [ 3 H]MK-801 binding since, under nonequilibrium conditions, this assay has been shown to be a sensitive and specific probe for effects at NMDA receptors. ,− Specifically, enhancement or inhibition of [ 3 H]MK-801 binding identifies substances that facilitate or reduce activity at the NMDA-gated calcium ion channel. ,− In overall agreement with the literature, , we found that in the nominal absence of glutamate and glycine (basal conditions) [ 3 H]MK-801 binding was enhanced by the addition of spermine. At an optimum concentration of 25 μM spermine, basal binding was increased between 350 and 1300%; basal binding decreased at higher concentrations of spermine.…”

Hydrothermal reactions: From the synthesis of ligand to new lanthanide 3D-coordination polymers

“…The ground state geometry was calculated with all three versions of the Sparkle Model [22][23][24][25]. The calculations were carried out considering periodic bound conditions aiming to obtain a solid state structure [25].…”

“…Sparkle/AM1 [22], Sparkle/PM3 [23] and Sparkle/PM6 [24] solid structure the X-ray diffraction simulations were performed. The structure obtained with the Sparkle/AM1 and PM6 models showed low level of agreement with the experimental result.…”

Current Scenario of 1,4-Diazepines as Potent Biomolecules-A Mini Review

“…Zhou et al reported N, N'disubstituted piperazine and homopiperazine derivatives with the objective of developing high-affinity polyamine site ligands that either facilitate or reduce activity at N-methyl-D-aspartate (NMDA) receptors. The homopiperazine compounds (26) showed polyamine-like actions by enhancing [ 3 H]MK-801 binding to NMDA receptors which are greater than compounds (27) [54]. The activation of NMDA receptors required for the induction of long-term potentiation in hippocampus, a process involved with learning and memory [55].…”