title: LNP 906, the first high-affinity photoaffinity ligand selective for I1 imidazoline receptors.
abstract: 1 The hypotensive effect of imidazoline-like drugs, such as clonidine, was attributed both to alpha2-adrenergic receptors and nonadrenergic imidazoline receptors, which are divided into I1, I2 and I3 subtypes. 2 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). 3 This work aims to test whether this derivative retained the binding properties of LNP 911 and bound irreversibly to I1R. 4 Binding studies showed that LNP 906 exhibited nanomolar affinity for I1R and was selective for I1R over I2 receptors and alpha2-adrenergic receptors (alpha2Ars). 5 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 alpha2 antagonist). 6 Finally, LNP 906 clearly antagonized the decrease in forskolin-stimulated cAMP level induced by rilmenidine, but not by melatonin. 7 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.
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, INSERM E 0333, Faculté de Médecine, Université Louis Pasteur, 11 rue Humann, 67000 Strasbourg, France.
authors.forename: Dragan
authors.initials: D
authors.lastname: Urosevic
authors.forename: Urosevic
authors.initials: U
authors.lastname: Dragan
authors.forename: Stephan
authors.initials: S
authors.lastname: Schann
authors.forename: Schann
authors.initials: S
authors.lastname: Stephan
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Ehrhardt
authors.forename: Ehrhardt
authors.initials: E
authors.lastname: Jean-Daniel
authors.forename: Pascal
authors.initials: P
authors.lastname: Bousquet
authors.forename: Bousquet
authors.initials: B
authors.lastname: Pascal
authors.forename: Hugues
authors.initials: H
authors.lastname: Greney
authors.forename: Greney
authors.initials: G
authors.lastname: Hugues
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001667:Binding, Competitive; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D054755:Imidazoline Receptors; D007457:Iodine Radioisotopes; D008024:Ligands; D016716:PC12 Cells; D019920:Photoaffinity Labels; D011759:Pyrrolidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism*; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: D001386:Azides; D054755:Imidazoline Receptors; D007457:Iodine Radioisotopes; C495453:LNP 906; D008024:Ligands; D019920:Photoaffinity Labels; D011759:Pyrrolidines; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; C410887:imidazoline I1 receptors; D000242:Cyclic AMP