Article date: June 2004
By: Urosevic Dragan, Schann Stephan, Ehrhardt Jean‐Daniel, Bousquet Pascal, Greney Hugues in Volume 142, Issue 3, pages 609-617
The hypotensive effect of imidazoline‐like drugs, such as clonidine, was attributed both to α2‐adrenergic receptors and nonadrenergic imidazoline receptors, which are divided into I1, I2 and I3 subtypes.
We have recently synthesized a derivative of (2‐(2‐chloro‐4‐iodo‐phenylamino)‐5‐methyl‐pyrroline (LNP 911), the first high‐affinity and selective ligand for I1 receptors (I1R), with a photoactivable function (LNP 906).
This work aims to test whether this derivative retained the binding properties of LNP 911 and bound irreversibly to I1R.
Binding studies showed that LNP 906 exhibited nanomolar affinity for I1R and was selective for I1R over I2 receptors and α2‐adrenergic receptors (α2Ars).
Upon exposure to u.v. light, LNP 906 irreversibly blocked the binding of [125I]‐paraiodoclonidine (PIC) to I1R, time‐ and dose‐dependently, on PC12 cell membranes and interacted with I1R in a reversible and competitive manner in the absence of light. Pharmacological studies showed that this blockade was prevented by the concomitant presence of rilmenidine (a well‐known I1 agonist), but not by rauwolscine (an α2 antagonist).
Finally, LNP 906 clearly antagonized the decrease in forskolin‐stimulated cAMP level induced by rilmenidine, but not by melatonin.
These results indicate that LNP 906 is the first high‐affinity and selective photoaffinity ligand for I1R and that it behaves as an I1R antagonist.
The hypotensive effect of imidazoline‐like drugs, such as clonidine, was attributed both to α2‐adrenergic receptors and nonadrenergic imidazoline receptors, which are divided into I1, I2 and I3 subtypes.
We have recently synthesized a derivative of (2‐(2‐chloro‐4‐iodo‐phenylamino)‐5‐methyl‐pyrroline (LNP 911), the first high‐affinity and selective ligand for I1 receptors (I1R), with a photoactivable function (LNP 906).
This work aims to test whether this derivative retained the binding properties of LNP 911 and bound irreversibly to I1R.
Binding studies showed that LNP 906 exhibited nanomolar affinity for I1R and was selective for I1R over I2 receptors and α2‐adrenergic receptors (α2Ars).
Upon exposure to u.v. light, LNP 906 irreversibly blocked the binding of [125I]‐paraiodoclonidine (PIC) to I1R, time‐ and dose‐dependently, on PC12 cell membranes and interacted with I1R in a reversible and competitive manner in the absence of light. Pharmacological studies showed that this blockade was prevented by the concomitant presence of rilmenidine (a well‐known I1 agonist), but not by rauwolscine (an α2 antagonist).
Finally, LNP 906 clearly antagonized the decrease in forskolin‐stimulated cAMP level induced by rilmenidine, but not by melatonin.
These results indicate that LNP 906 is the first high‐affinity and selective photoaffinity ligand for I1R and that it behaves as an I1R antagonist.
British Journal of Pharmacology (2004) 142, 609–617. doi:10.1038/sj.bjp.0705784
DOI: 10.1038/sj.bjp.0705784
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