Polyamine regulation of the NMDA receptor complex as a target in drug development (original) (raw)
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New polyamine-sensitive inhibitors of the NMDA receptor: Syntheses and pharmacological evaluation
European Journal of Medicinal Chemistry, 2007
Derivatives of 5-(4-aminobutyl)-2-thiophene-octylamine, a potent polyamine-sensitive inhibitor of the NMDA receptor, were synthesized and evaluated as inhibitors of [ 3 H]MK-801 binding to rat brain membranes. Alkylations of the terminal amino groups reduced inhibitory potency; only incorporation of the amino group of the short 4-aminobutyl arm into a piperidine ring was tolerated. Substitution of the thiophene nucleus with methyl or ethyl, and its replacement by a benzene nucleus, was of minor influence. The corresponding diguanidines exhibited high potency independent of chain length, whereas their sensitivity to spermine was sharply dependent on chain length. Insertion of an amide bond into the long octylamine arm increased sensitivity to spermine and to Tris buffer. Our results indicate that spermine sensitivity of [ 3 H]MK-801 binding inhibition is responsive to subtle changes in inhibitor structure and represents a promising target for pharmaceutical research.
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
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.
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.
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.
Polyamines modulate the neurotoxic effects of NMDA in vivo
Brain Research, 1993
The ability of polyamines to alter NMDA-induced neurotoxicity in neonatal rats was examined to determine whether polyamines modulate NMDA receptor activity in vivo. Unilateral injections of NMDA and/or polyamines were made into the striatum of 7-day-old rats. After 5 days, the brains were removed and 20/.~m thick coronal sections were cut and stained with Cresyl violet. A computer-based image analysis system was used to densitometrically measure the cross-sectional area of intact tissue in the control and injected hemispheres. Administration of NMDA (5-40 nmol) produced a dose-dependent tissue damage that ranged from 7 to 52% of the area of the uninjected hemisphere. The polyamine agonist spermine (10-500 nmol) dose-dependently exacerbated the toxicity of a 15 nmol dose of NMDA, increasing the size of the lesion by up to 50%. Administration of spermine alone produced dose-dependent tissue damage that ranged from 9 to 52%. The damage produced by both NMDA and spermine could be completely inhibited by co-administration of the NMDA antagonist MK-801. The polyamine inverse agonist 1,10-diaminodecane (DA-10, 50-400 nmol) inhibited the damage produced by NMDA in a dose-dependent manner, with a maximal inhibition of 50%. Administration of DA-10 alone produced limited damage at doses above 100 nmol. The weak partial agonist diethylenetriamine had no effect by itself or on NMDA-induced toxicity at the doses tested. These results indicate that polyamines can modulate the activity of NMDA receptors in vivo and suggest that polyamines or related compounds may have important therapeutic potential as neuroprotective agents.
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.
Neuroscience Letters, 1992
In the present study, we have examined by light and electron microscopy whether SL 82.0715, a polyamine site-directed N-methyl-D-aspartate (NMDA) antagonist, causes pathological changes in cerebrocortical neurons similar to those observed with NMDA receptor channel blockers in the rat brain. Dizocilpine (1, 2 and 5 mg.kg-1, s.c.) induced a dose-dependent vacuolization of the neuronal cytoplasm in specific neurons of the retrosplenial and posterior cingulate cortices (layers III and IV) even at the lowest dose studied, at 6 h post-injection. In contrast, SL 82.0715 (10 and 30 mg.kg-1 i.p., 6 h post-injection) did not induce such morphological alterations. These results indicate that NMDA receptor blockade is not necessarily associated with alterations of cortical neuronal morphology.