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Molecular Pharmacology

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Research ArticleArticle

[125I]2-(2-Chloro-4-iodo-phenylamino)-5-methyl-pyrroline (LNP 911), a High-Affinity Radioligand Selective for I1Imidazoline Receptors

Hugues Greney, Dragan Urosevic, Stephan Schann, Laurence Dupuy, Véronique Bruban, Jean-Daniel Ehrhardt, Pascal Bousquet and Monique Dontenwill
Molecular Pharmacology July 2002, 62 (1) 181-191; DOI: https://doi.org/10.1124/mol.62.1.181
Hugues Greney
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Medecine, Strasbourg, France
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Dragan Urosevic
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Medecine, Strasbourg, France
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Stephan Schann
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Medecine, Strasbourg, France
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Laurence Dupuy
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Medecine, Strasbourg, France
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Véronique Bruban
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Medecine, Strasbourg, France
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Jean-Daniel Ehrhardt
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Medecine, Strasbourg, France
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Pascal Bousquet
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Medecine, Strasbourg, France
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Monique Dontenwill
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Medecine, Strasbourg, France
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Abstract

The I1 subtype of imidazoline receptors (I1R) is a plasma membrane protein that is involved in diverse physiological functions. Available radioligands used so far to characterize the I1R were able to bind with similar affinities to α2-adrenergic receptors (α2-ARs) and to I1R. This feature was a major drawback for an adequate characterization of this receptor subtype. New imidazoline analogs were therefore synthesized and the present study describes one of these compounds, 2-(2-chloro-4-iodo-phenylamino)-5-methyl-pyrroline (LNP 911), which was of high affinity and selectivity for the I1R. LNP 911 was radioiodinated and its binding properties characterized in different membrane preparations. Saturation experiments with [125I]LNP 911 revealed a single high affinity binding site in PC-12 cell membranes (K D = 1.4 nM;B max = 398 fmol/mg protein) with low nonspecific binding. [125I]LNP 911 specific binding was inhibited by various imidazolines and analogs but was insensitive to guanosine-5′-O-(3-thio)triphosphate. The rank order of potency of some competing ligands [LNP 911, PIC, rilmenidine, 4-chloro-2-(imidazolin-2-ylamino)-isoindoline (BDF 6143), lofexidine, and clonidine] was consistent with the definition of [125I]LNP 911 binding sites as I1R. However, other high-affinity I1R ligands (moxonidine, efaroxan, and benazoline) exhibited low affinities for these binding sites in standard binding assays. In contrast, when [125I]LNP 911 was preincubated at 4°C, competition curves of moxonidine became biphasic. In this case, moxonidine exhibited similar high affinities on [125I]LNP 911 binding sites as on I1R defined with [125I]PIC. Moxonidine proved also able to accelerate the dissociation of [125I]LNP 911 from its binding sites. These results suggest the existence of an allosteric modulation at the level of the I1R, which seems to be corroborated by the dose-dependent enhancement by LNP 911 of the agonist effects on the adenylate cyclase pathway associated to I1R. Because [125I]LNP 911 was unable to bind to the I2binding site and α2AR, our data indicate that [125I]LNP 911 is the first highly selective radioiodinated probe for I1R with a nanomolar affinity. This new tool should facilitate the molecular characterization of the I1 imidazoline receptor.

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Molecular Pharmacology: 62 (1)
Molecular Pharmacology
Vol. 62, Issue 1
1 Jul 2002
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Research ArticleArticle

[125I]2-(2-Chloro-4-iodo-phenylamino)-5-methyl-pyrroline (LNP 911), a High-Affinity Radioligand Selective for I1Imidazoline Receptors

Hugues Greney, Dragan Urosevic, Stephan Schann, Laurence Dupuy, Véronique Bruban, Jean-Daniel Ehrhardt, Pascal Bousquet and Monique Dontenwill
Molecular Pharmacology July 1, 2002, 62 (1) 181-191; DOI: https://doi.org/10.1124/mol.62.1.181

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Research ArticleArticle

[125I]2-(2-Chloro-4-iodo-phenylamino)-5-methyl-pyrroline (LNP 911), a High-Affinity Radioligand Selective for I1Imidazoline Receptors

Hugues Greney, Dragan Urosevic, Stephan Schann, Laurence Dupuy, Véronique Bruban, Jean-Daniel Ehrhardt, Pascal Bousquet and Monique Dontenwill
Molecular Pharmacology July 1, 2002, 62 (1) 181-191; DOI: https://doi.org/10.1124/mol.62.1.181
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