New polyamine-sensitive inhibitors of the NMDA receptor: Syntheses and pharmacological evaluation (original) (raw)
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Polyamine regulation of the NMDA receptor complex as a target in drug development
Medicinal Chemistry, 2003
The NMDA receptor complex (NR) is one of the main targets of the excitatory neurotransmitter glutamic acid. A partial block of the NR by protons even at physiological pH can by removed by the natural polyamines (PAs) spermidine and spermine. Several unbranched diamines as arcaine and 1,12-dodecanediamine (N12N) seem to block the NR (at least to some extent) via the same mechanism (polyamine inverse agonists). Systematic structural modification led to the discovery of 5-(4-aminobutyl)-2-thiopheneoctanamine (N4T8N), one of the most potent compounds in this family (IC50 0.3 µM). Via allosteric sites, ifenprodil and zinc increase the sensitivity of the NR to proton inhibition, blocking the NR in apparent competition with stimulating PAs. Here, the recent literature is reviewed on compounds interacting directly or indirectly with PA regulation of the NR.
Neuroscience Letters, 1996
The amino-1-oxy-and amino-8-oxy-analogues of spermidine (1-O-SPD and 8-O-SPD) were tested in vitro with rat hippocampal membranes as potential modulators of the N-methyl-D-aspartate (NMDA) receptor complex via the polyamine regulatory site. In the presence of 1/~M glutamate and glycine, the binding of the NMDA channel ligand [3H]MK-801 was stimulated by 8-O-SPD (ECs0 = 50ktM); 1-O-SPD was without significant influence at concentrations up to 1 mM. Addition of 2 and 4/~M of the polyamine agonist spermine eliminated the stimulatory property of 8-O-SPD, whereas 1-O-SPD was inhibitory under these conditions (IC5o = 274 and 481 ktM, respectively). At higher concentrations of spermine, both compounds were inhibitory. Inhibition of [3H]MK-801 binding by the inverse polyamine agonists 1,10-diaminodecane, 1,12-diaminododecane, and arcaine was attenuated by 1 mM 1-O-SPD. The data are compatible with the notion that 8-O-SPD is a partial polyamine agonist and that I-O-SPD is an antagonist without intrinsic activity.
Bioorganic & Medicinal Chemistry, 2015
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.
Molecular Features Associated with Polyamine Modulation of NMDA Receptors
Journal of Medicinal Chemistry, 1998
The effect of 1,3-diamines on basal and spermine-stimulated [ 3 H]MK-801 binding was investigated. Systematic variations in the molecular parameters revealed that, in general, lipophilic 1,3-diamines inhibited and hydrophilic 1,3-diamines enhanced [ 3 H]MK-801 binding in the nominal absence of glutamate and glycine. Furthermore, 1,3-diamines which were highly monoprotonated at physiologic pH were more effective in modulating basal binding (at 100 µM 1,3-diamine) than analogues which were mostly diprotonated or unprotonated. Finally, the internuclear distance between the amino nitrogens and the extent of modulation of basal [ 3 H]MK-801 binding were correlated. Similar, but more modest, effects were seen for spermineenhanced [ 3 H]MK-801 binding. These results are consistent with the existence of two polyamine binding sites associated with the NMDA receptor complex. One of the sites appears to preferentially recognize lipophilic substances while the other favors hydrophilic materials. Both sites appear to recognize polyamines with at least one charged (protonated) amino group and one uncharged amino group. The distance between amino groups is a determining factor as well.
Chemical and Pharmaceutical Bulletin, 2010
Three pharmacologically-defined classes of ionotropic glutamate receptors were originally named according to their agonist selectivity: N-methyl-D-aspartate (NMDA), a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate. The NMDA receptor consists of at least two distinct subunits, NR1 and NR2 1) (Fig. 1A). Each subunit has three transmembrane domains (M1, M3, and M4) plus a cytoplasm-facing re-entrant membrane loop (M2). The M2 loop region in the NR1 and NR2 subunits is a critical determinant of divalent cation permeability and Mg 2ϩ block. NR1 is a single gene product expressed as eight alternatively spliced mRNAs, and NR2A, NR2B, NR2C and NR2D are distinct gene products. NMDA receptors probably consist of tetrameric subunit assemblies that have different physiological and pharmacological properties depending on the specific NR2 subunit. In the central nervous system, NMDA receptors play critical roles in a variety of neurophysiological phenomena, including neurodevelopment, synaptic plasticity, and excitotoxicity, because of their high permeability to Ca 2ϩ. Neurodegeneration associated with a variety of acute and chronic disorders (e.g., ischemic stroke, Parkinson's disease, Alzheimer's disease and dementia) is due in part to overactivation of NMDA receptors (Fig. 1B). Inhibitors of NMDA receptors have thus been developed as anticonvulsants and neuroprotective agents. Polyamines (putrescine, spermidine and spermine) are ubiquitously present in prokaryotic and eukaryotic cells. In the central nervous system, specific interactions of polyamines with several structurally and functionally distinct types of cation channels have been reported previously. 2) Among these, the most striking are the blockade of some types of K ϩ channels and the modulation of NMDA receptors. Spermine has complex effects on NMDA receptors, including two types of stimulation and one type of voltage-dependent blockade. One of the effects of spermine is "glycineindependent" stimulation, observed in the presence of saturating concentrations of glutamate and glycine. With recombinant NMDA receptors, this type of stimulation is observed only at receptors containing splice variants of NR1 that lack the exon-5 insert, expressed together with the NR2B subunit. 3) Inhibition by extracellular spermine is strongly voltage-dependent, being more pronounced at hyperpolarized
Preparation and testing of homocubyl amines as therapeutic NMDA receptor antagonists
Computational modeling demonstrates that the van-der-Waals surfaces of homocubyl amines are similar to that of the neuroprotector Memantine Ò . Utilizing readily available precursors we report the preparation of a series of homological cubylamines, namely pentacyclo[6.3.0.0 2,6 .0 3,10 .0 5,9 ]undecyl-4-amine (trishomocubyl-4-amine, 2), pentacyclo[5.3.0.0 2,5 . 0 3,9 .0 4,8 ]decyl-10-amine (bishomocubyl-10-amine, 3), pentacyclo[4.3.0.0 2,5 .0 3,8 .0 4,7 ]nonyl-9-amine (homocubyl-9-amine, 4), and pentacyclo[4.2.0.0 2,5 .0 3,8 .0 4,7 ]octyl-1-amine (cubylamine, 5). The hydrochlorides of amines 2-5 show pronounced affinity for the (?)MK-801 channel binding site, and it seems likely that these compounds would act as very fast voltagedependent NMDA receptor antagonists.
Bioorganic & Medicinal Chemistry Letters, 2013
The biological activities of six symmetrically substituted 2-methoxy-benzyl polymethylene tetraamines (1-4) and diphenylethyl polymethylene tetraamines (5 and 6) as N-methyl-D-aspartate (NMDA) receptor channel blockers, were evaluated in vitro and in vivo. Although all compounds exhibited stronger channel block activities in comparison to memantine in Xenopus oocytes voltage clamped at À70 mV, only compound 2 (0.4 mg/kg intravenous injection) decreased the size of brain infarction in a photochemically induced thrombosis model mice at the same extent of memantine (10 mg/kg intravenous injection). Other compounds (1, 3, 4, 5 and 6) did not decrease the size of brain infarction significantly due to the limited injection doses. The present study suggests that compound 2 could represent a valuable lead compound to design low toxicity polyamines for clinical use against stroke.
Novel bisbenzamidines and bisbenzimidazolines as noncompetitive NMDA receptor antagonists
Bioorganic & Medicinal Chemistry Letters, 1999
A series of novel bisbenzamidines and bisbenzimidazolines with different linkers connecting the aromatic groups was tested in vitro for NMDA receptor antagonist activity. IC~0 values for these compounds ranged from 1.2 to >200 }aM. The bisbenzamidine with a homopiperazine ring as the central linker was found to be the most potent NMDA receptor antagonist among all the pentamidine analogues tested so far.
Brain Research, 1991
Polyamines such as spermidine potentiate activation of the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. The goal of the present study was to investigate interactions between the putative polyamine binding site and previously described sites for glutamate and glycine. Binding of the high-potency PCP receptor ligand [3H]MK-801 to well-washed rat brain membranes was used as an in vitro probe of NMDA receptor activation. Spermidine concentration-response studies were performed in the absence and presence of both glutamate and glycine, with and without D-(-)-2-amino-5-phosphonovaleric acid (D(-)AP-5) or 7-chiorokynurenic acid (7C1-KYN). Incubation in the presence of spermidine alone induced a 20.4-fold increase in [3H]MK-801 binding with an ECs0 value of 13.3/~M. The mean concentration of spermidine which induced maximal stimulation of binding was 130/~M (n = 10, S.E.M. = 24.66, range = 25-250 ktM). Glutamate (10 /zM) decreased the ECs0 value for spermidine-induced stimulation of [3H]MK-801 binding to 3.4/~M. Glycine (10 ktM) did not significantly alter either maximum spermidine-induced [3H]MK-801 binding or the ECso value for spermidine-induced stimulation of [3H]MK-801 binding. Incubation in the presence of the specific glutamate antagonist D(-)AP-5 attenuated [3H]MK-801 binding in a glutamate-reversible fashion. The competitive glycine antagonist 7CI-KYN decreased maximum spermidine-induced [ 3H]MK-801 binding in a glycine-reversible fashion. In addition, 7CI-KYN increased the ECso value for spermidine-induced stimulation of [3H]MK-801 binding while D(-)AP-5 was without effect. These findings suggest that glutamate and glycine regulate the polyamine binding site differentially. PCP-like agents induce a psychotomimetic state closely resembling schizophrenia by inhibiting NMDA receptor-mediated neurotransmission. The ability of polyamines to modulate NMDA receptor functioning suggests a potential site for pharmacological intervention.