Potent enhancement of [3H]nitrendipine binding in rat cerebral cortical and cardiac homogenates: A putative mechanism for the action of MDL 12,330A

H. R. Lee, J. A. Jaros, William R Roeske

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Abstract

[3H]Nitrendipine ([3H]NTD), a specific high-affinity calcium channel antagonist, was used to label dihydropyridine binding sites associated with calcium channels in rat cerebral cortical and cardiac homogenates. A novel lactamimide compound, MDL 12,33A, has been shown previously to have negative inotropic and chronotropic effects in isolated working guinea-pig hearts and these effects are reversed by the administration of calcium. MDL 12,330A is potent in enhancing [3H]NTD binding in membranes prepared from the cerebral cortex and the heart, with EC50 values of 6.1 x 10-8 and 3.4 x 10-8M, respectively, at 37°C. This allosteric effect by MDL 12,330A is similar to that produced by a known calcium channel antagonist, d-cis diltiazem, which has been shown previously to enhance [3H]NTD binding at 37°C. The extent of enhancement by MDL 12,330A depends on incubation temperature (37°C>25°C>0°C). The mechanism of this enhancement by MDL 12,330A is due to a decrease in the dissociation rate constant of the dihydropyridine-calcium channel supramolecular complex. MDL 12,330A is the most potent drug thus far examined which demonstrates the enhancement of [3H]NTD binding.

Original languageEnglish (US)
Pages (from-to)611-616
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume233
Issue number3
StatePublished - 1985

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Nitrendipine
Calcium Channel Blockers
Calcium Channels
Diltiazem
Cerebral Cortex
Guinea Pigs
Binding Sites
RMI 12330A
Calcium
Temperature
Membranes
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

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abstract = "[3H]Nitrendipine ([3H]NTD), a specific high-affinity calcium channel antagonist, was used to label dihydropyridine binding sites associated with calcium channels in rat cerebral cortical and cardiac homogenates. A novel lactamimide compound, MDL 12,33A, has been shown previously to have negative inotropic and chronotropic effects in isolated working guinea-pig hearts and these effects are reversed by the administration of calcium. MDL 12,330A is potent in enhancing [3H]NTD binding in membranes prepared from the cerebral cortex and the heart, with EC50 values of 6.1 x 10-8 and 3.4 x 10-8M, respectively, at 37°C. This allosteric effect by MDL 12,330A is similar to that produced by a known calcium channel antagonist, d-cis diltiazem, which has been shown previously to enhance [3H]NTD binding at 37°C. The extent of enhancement by MDL 12,330A depends on incubation temperature (37°C>25°C>0°C). The mechanism of this enhancement by MDL 12,330A is due to a decrease in the dissociation rate constant of the dihydropyridine-calcium channel supramolecular complex. MDL 12,330A is the most potent drug thus far examined which demonstrates the enhancement of [3H]NTD binding.",
author = "Lee, {H. R.} and Jaros, {J. A.} and Roeske, {William R}",
year = "1985",
language = "English (US)",
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journal = "Journal of Pharmacology and Experimental Therapeutics",
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T1 - Potent enhancement of [3H]nitrendipine binding in rat cerebral cortical and cardiac homogenates

T2 - A putative mechanism for the action of MDL 12,330A

AU - Lee, H. R.

AU - Jaros, J. A.

AU - Roeske, William R

PY - 1985

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AB - [3H]Nitrendipine ([3H]NTD), a specific high-affinity calcium channel antagonist, was used to label dihydropyridine binding sites associated with calcium channels in rat cerebral cortical and cardiac homogenates. A novel lactamimide compound, MDL 12,33A, has been shown previously to have negative inotropic and chronotropic effects in isolated working guinea-pig hearts and these effects are reversed by the administration of calcium. MDL 12,330A is potent in enhancing [3H]NTD binding in membranes prepared from the cerebral cortex and the heart, with EC50 values of 6.1 x 10-8 and 3.4 x 10-8M, respectively, at 37°C. This allosteric effect by MDL 12,330A is similar to that produced by a known calcium channel antagonist, d-cis diltiazem, which has been shown previously to enhance [3H]NTD binding at 37°C. The extent of enhancement by MDL 12,330A depends on incubation temperature (37°C>25°C>0°C). The mechanism of this enhancement by MDL 12,330A is due to a decrease in the dissociation rate constant of the dihydropyridine-calcium channel supramolecular complex. MDL 12,330A is the most potent drug thus far examined which demonstrates the enhancement of [3H]NTD binding.

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