Two allosteric modulators interact at a common site on cardiac muscarinic receptors

John Ellis, M. Seidenberg

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

The abilities of gallamine, obidoxime, tetrahydroaminoacridine (THA), and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) to alter the rate of dissociation of N-[3H]methylscopolamine from rat cardiac muscarinic receptors were investigated. All four ligands monotonically slowed the dissociation, with the order of potency gallamine > TMB-8 > THA > obidoxime. There was a dramatic difference in the efficacy of these allosteric modulators. Gallamine, TMB-8, and THA slowed the dissociation of N- methylscopolamine by >90% at maximally effective concentrations, whereas obidoxime was capable of slowing it by only about 50%. In a manner analogous to the action of a partial agonist, obidoxime was able to partially reverse the effects of the other three modulators. Furthermore, the concentration- dependent effects of combinations of obidoxime and gallamine were in good agreement with the model of competitive interaction between these two ligands. These results provide the first evidence that two muscarinic allosteric modulators interact competitively at a well defined site.

Original languageEnglish (US)
Pages (from-to)638-641
Number of pages4
JournalMolecular Pharmacology
Volume42
Issue number4
StatePublished - 1992

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Obidoxime Chloride
Gallamine Triethiodide
Muscarinic Receptors
Tacrine
N-Methylscopolamine
Ligands
Cholinergic Agents
8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

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title = "Two allosteric modulators interact at a common site on cardiac muscarinic receptors",
abstract = "The abilities of gallamine, obidoxime, tetrahydroaminoacridine (THA), and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) to alter the rate of dissociation of N-[3H]methylscopolamine from rat cardiac muscarinic receptors were investigated. All four ligands monotonically slowed the dissociation, with the order of potency gallamine > TMB-8 > THA > obidoxime. There was a dramatic difference in the efficacy of these allosteric modulators. Gallamine, TMB-8, and THA slowed the dissociation of N- methylscopolamine by >90{\%} at maximally effective concentrations, whereas obidoxime was capable of slowing it by only about 50{\%}. In a manner analogous to the action of a partial agonist, obidoxime was able to partially reverse the effects of the other three modulators. Furthermore, the concentration- dependent effects of combinations of obidoxime and gallamine were in good agreement with the model of competitive interaction between these two ligands. These results provide the first evidence that two muscarinic allosteric modulators interact competitively at a well defined site.",
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Two allosteric modulators interact at a common site on cardiac muscarinic receptors. / Ellis, John; Seidenberg, M.

In: Molecular Pharmacology, Vol. 42, No. 4, 1992, p. 638-641.

Research output: Contribution to journalArticle

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