Showing papers on "Polyamine binding published in 2000"

Polyamine analogues as therapeutic and diagnostic agents

Abstract: Novel inhibitors of polyamine transport having inhibition constants two orders of magnitude lower than those of known compounds are disclosed. These polyamine analogues are useful pharmaceutical agents for treating diseases where it is desired to inhibit polyamine transport or other polyamine binding proteins, for example cancer and post-angioplasty injury. Novel chemical synthetic methods to obtain polyamine analogues are disclosed, including the production of a combinational polyamine library. These approaches yield analogues with desirable activities both for diagnostic and research assays and therapy. The assays of the invention are useful for high throughput screening of targets in the discovery of drugs that interact with the polyamine system.

Intrahippocampal spermidine administration improves inhibitory avoidance performance in rats.

Abstract: Polyamines are polycations present at high concentrations in the mammalian brain. We investigated the effect of an intrahippocampal infusion of spermidine, a polyamine agonist, immediately post-training on the inhibitory avoidance learning paradigm in rats. Bilateral intrahippocampal microinjection of spermidine (0.02-20 nmol) caused an increase in test step-down latencies at low concentrations. Administration of arcaine (0.002-0.2 nmol), an antagonist of the N-methyl-D-aspartate (NMDA) receptor polyamine binding site, did not modify the test step-down latencies. In contrast, co-administration of arcaine and spermidine completely reversed the facilitatory effect of spermidine on the test step-down latencies. These results provide evidence that polyamines may be involved in learning and memory modulation.

Photoaffinity polyamines: interactions with AcPhe-tRNA free in solution or bound at the P-site of Escherichia coli ribosomes.

Abstract: Two photoreactive derivatives of spermine, azidobenzamidino (ABA)-spermine and azidonitrobenzoyl (ANB)-spermine, were used for mapping of polyamine binding sites in AcPhe-tRNA free in solution or bound at the P-site of Escherichia coli poly(U)-programmed ribosomes. Partial nuclease digestion indicated that the deep pocket formed by nucleosides of the D-stem and the variable loop, as well as the anticodon stem, are preferable polyamine binding sites for AcPhe-tRNA in the free state. ABA-spermine was a stronger cross-linker than ANB-spermine. Both photoprobes were linked to AcPhe-tRNA with higher affinity when the latter was non-enzymatically bound to poly(U)-programmed ribosomes. In particular, the cross-linking at the TψC stem and acceptor stem was substantially promoted. The photolabeled AcPhe-tRNA·poly(U)·ribosome complex exhibited moderate reactivity towards puromycin. The attachment of photoprobes to AcPhe-tRNA was mainly responsible for this defect. A more complicated situation was revealed when the AcPhe-tRNA·poly(U)·ribosome complex was formed in the presence of translation factors; the reactivity towards puromycin was stimulated by irradiating such a complex in the presence of photoprobes at 50 µM, with higher concentrations being inhibitory. The stimulatory effect was closely related with the binding of photoprobes to ribosomes. The results are discussed on the basis of possible AcPhe-tRNA conformational changes induced by the incorporation of photoprobes.

Dapsone analogs as potential polyamine binding site modulators of the N-methyl-D-aspartate receptor complex

Abstract: A high-throughput radioligand binding assay was used to screen a series of dapsone analogs for their capacity to displace [3H]-spermidine and [3H]-MK-801 from their respective binding sites on the N-methyl-D-aspartate (NMDA) receptor complex in rat brain homogenates. Dapsone did not alter [3H]-spermidine or [3H]-MK-801 binding, suggesting that the neuroprotective properties that have been attributed to this compound may not be due to modulation of the NMDA receptor complex at the polyamine binding site. In contrast, structural analogs of dapsone, including N-phenyl-1,4-phenyldiamine and 4,4′diaminoazobenzene, effectively displaced [3H]-SPD and [3H]-MK-801. These active dapsone analogs may represent a new class of polyamine binding site ligands that may provide opportunities for the rational design of novel NMDA receptor modulators. Drug Dev. Res. 51:268–272, 2000. © 2001 Wiley-Liss, Inc.

[Bis-ammonium adamantane derivatives--novel modulators of polyamine binding sites].

Abstract: Experiments on intact rats and mice showed that the polyamine agonist spermine and the bis-ammonium adamantyl-containing compounds IEM-1460 and IEM-1754 potentiate the NMDA induced analgesia and convulsions and eliminate the analgesic effects of nicotine and kainate. Arcain, a competitive polyamine antagonist, eliminated (at the same dose) the activating and blocking effects of spermine, IEM-1460 and IEM-1754. In small doses, IEM-1754 (similarly to arcain) removed the analgesic effect of NMDA. It is suggested that IEM-1460 (similarly to spermine) is a polyamine agonist, while IEM-1754 is an antagonist/agonist of the polyamine site of NMDA, AMPA/kainate, and nicotinic receptors. The potentiating activity of IEM-1460 is two orders higher as compared to that of spermine.

Non-N-methyl-D-aspartate (NMDA) receptor antagonist 1,2,3, 4-tetrahydro-6-nitro-2,3-dioxo-benzo(f)quinoxaline-7-sulphonamide (NBQX) decreases functional disorders in cytotoxic brain oedema.

Abstract: N-methyl-D-aspartate (NMDA) and non-NMDA receptors were found to be involved in development of functional disorders caused by hexachlorophene. In order to specify the role of glutamate receptors we studied the protective effects of the selective antagonist of the kainate/(±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor/channel 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide disodium (NBQX) and of the non-competitive NMDA receptor antagonist ifenprodil tartrate on coordinative motor behaviour of adult male Wistar rats as assessed in a simple `ladder-test'. Neurotoxic injury of the cerebrum after hexachlorophene administration and putative amelioration after treatment with test substances was demonstrated histologically. Hexachlorophene-induced motor disturbance remitted spontaneously when stopping the noxis, but remittance occurred significantly earlier when NBQX [0.45 and 0.6 mg/kg intraperitoneal (i.p.)] was applied as well. Ifenprodil (0.15 to 1.2 mg/kg) did not improve the motor function. Vacuolation of white matter of the whole cerebrum was observed after 3 weeks of treatment with hexachlorophene. These morphological alterations caused by hexachlorophene treatment [central nervous system (CNS) vacuolation] spontaneously revert only after 5–6 weeks. The 5-day duration with test substances was too short for remission of vacuolation which thus may not apply to the situation after treatment with glutamate antagonists, despite improvement of motor function. The results suggest that kainate/AMPA receptor channels are at least partially involved in the mechanism of brain damage induced by hexachlorophene, however, the polyamine binding site of the NMDA receptor evidently is not involved.