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 a 2 -adrenergic receptors and nonadrenergic imidazoline receptors, which are divided into I 1 , I 2 and I 3 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 I 1 receptors (I 1 R), 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 I 1 R. 4 Binding studies showed that LNP 906 exhibited nanomolar affinity for I 1 R and was selective for I 1 R over I 2 receptors and a 2 -adrenergic receptors (a 2 Ars). 5 Upon exposure to u.v. light, LNP 906 irreversibly blocked the binding of [ 125 I]-paraiodoclonidine (PIC) to I 1 R, time-and dose-dependently, on PC12 cell membranes and interacted with I 1 R 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 I 1 agonist), but not by rauwolscine (an a 2 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 I 1 R and that it behaves as an I 1 R antagonist.

Synthesis of 1-pyrroline derivatives via cyclization of terminal alkynes with 2-azaallyls

“…1 Among them, 1-pyrrolines and their analogues are important pharmacophores present in biologically active compounds and natural alkaloids. They have gained a great deal of attention due to their extensive pharmaceutical activity and biological significance (lanopylin B1, 2 LNP911/LNP906, 3 iminosaccharide, 4 and broussonetine U and U1, 5 Fig. 1).…”