Abstract
Spermidine and spermine, as well as several other structurally related compounds, were tested in a [3H]N-(1-[thienyl]cyclohexyl) piperidine ([3H]TCP) binding assay to determine the structural requirements of polyamines for activation of the N-methyl-D-aspartate-operated ion channel. Under nonequilibrium conditions, the polyamines enhanced [3H]TCP binding approximately 9-fold, with EC50 values ranging from 0.8 to 60 μM. The order of potency in enhancing [3H]TCP binding was N,N′-bis(3-aminopropyl)-1,3-propanediamine > N,N′-bis-(3-aminopropyl)-ethylenediamine > spermine > spermidine > N,N′-bis-(2-aminoethyl)-1,3-propanediamine. 1,3-Diaminopropane produced a partial agonistic effect, whereas putrescine, cadaverine, and 1,7-diaminoheptane were without effect at concentrations up to 1 mM. Eadie-Hofstee analysis of spermidine-induced [3H]TCP binding at equilibrium revealed a 3-fold increase in the affinity without a significant change in receptor density. This was further supported by kinetic data that showed that spermidine produced an increase in the association rate and a decrease in the dissociation rate of [3H]TCP binding to its site. Putrescine, cadaverine, and 1,3-diaminopropane antagonized the effects of spermidine by an apparently noncompetitive mechanism. Magnesium ions mimicked the effects of putrescine, suggesting the possibility that the inhibitory effects of Mg2+ and putrescine are mechanistically related.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 572-577 |
| Number of pages | 6 |
| Journal | Molecular Pharmacology |
| Volume | 37 |
| Issue number | 4 |
| State | Published - Apr 1990 |
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ASJC Scopus subject areas
- Pharmacology
Cite this
Characterization of the stimulatory and inhibitory effects of polyamines on [3H]N-(1-[thienyl]cyclohexyl) piperidine binding to the N-Methyl-D-aspartate receptor ionophore complex. / Sacaan, Aida I.; Johnson, Kenneth M.
In: Molecular Pharmacology, Vol. 37, No. 4, 04.1990, p. 572-577.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Characterization of the stimulatory and inhibitory effects of polyamines on [3H]N-(1-[thienyl]cyclohexyl) piperidine binding to the N-Methyl-D-aspartate receptor ionophore complex
AU - Sacaan, Aida I.
AU - Johnson, Kenneth M.
PY - 1990/4
Y1 - 1990/4
N2 - Spermidine and spermine, as well as several other structurally related compounds, were tested in a [3H]N-(1-[thienyl]cyclohexyl) piperidine ([3H]TCP) binding assay to determine the structural requirements of polyamines for activation of the N-methyl-D-aspartate-operated ion channel. Under nonequilibrium conditions, the polyamines enhanced [3H]TCP binding approximately 9-fold, with EC50 values ranging from 0.8 to 60 μM. The order of potency in enhancing [3H]TCP binding was N,N′-bis(3-aminopropyl)-1,3-propanediamine > N,N′-bis-(3-aminopropyl)-ethylenediamine > spermine > spermidine > N,N′-bis-(2-aminoethyl)-1,3-propanediamine. 1,3-Diaminopropane produced a partial agonistic effect, whereas putrescine, cadaverine, and 1,7-diaminoheptane were without effect at concentrations up to 1 mM. Eadie-Hofstee analysis of spermidine-induced [3H]TCP binding at equilibrium revealed a 3-fold increase in the affinity without a significant change in receptor density. This was further supported by kinetic data that showed that spermidine produced an increase in the association rate and a decrease in the dissociation rate of [3H]TCP binding to its site. Putrescine, cadaverine, and 1,3-diaminopropane antagonized the effects of spermidine by an apparently noncompetitive mechanism. Magnesium ions mimicked the effects of putrescine, suggesting the possibility that the inhibitory effects of Mg2+ and putrescine are mechanistically related.
AB - Spermidine and spermine, as well as several other structurally related compounds, were tested in a [3H]N-(1-[thienyl]cyclohexyl) piperidine ([3H]TCP) binding assay to determine the structural requirements of polyamines for activation of the N-methyl-D-aspartate-operated ion channel. Under nonequilibrium conditions, the polyamines enhanced [3H]TCP binding approximately 9-fold, with EC50 values ranging from 0.8 to 60 μM. The order of potency in enhancing [3H]TCP binding was N,N′-bis(3-aminopropyl)-1,3-propanediamine > N,N′-bis-(3-aminopropyl)-ethylenediamine > spermine > spermidine > N,N′-bis-(2-aminoethyl)-1,3-propanediamine. 1,3-Diaminopropane produced a partial agonistic effect, whereas putrescine, cadaverine, and 1,7-diaminoheptane were without effect at concentrations up to 1 mM. Eadie-Hofstee analysis of spermidine-induced [3H]TCP binding at equilibrium revealed a 3-fold increase in the affinity without a significant change in receptor density. This was further supported by kinetic data that showed that spermidine produced an increase in the association rate and a decrease in the dissociation rate of [3H]TCP binding to its site. Putrescine, cadaverine, and 1,3-diaminopropane antagonized the effects of spermidine by an apparently noncompetitive mechanism. Magnesium ions mimicked the effects of putrescine, suggesting the possibility that the inhibitory effects of Mg2+ and putrescine are mechanistically related.
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M3 - Article
VL - 37
SP - 572
EP - 577
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 4
ER -