Synthesis and characterization of arylamine derivatives of rauwolscine as molecular probes for α<inf>2</inf>-adrenergic receptors

Stephen M. Lanier, Robert M. Graham, Hans Ju¨rgen Hess, Alex Grodski, Mary G. Repaske, Jodi M. Nunnari, Lee E. Limbird, Charles J. Homcy

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The selective α<inf>2</inf>-adrenergic receptor antagonist rauwolscine was structurally modified to yield a series of arylamine carboxamide derivatives, which were investigated as potential molecular probes for the localization and structural characterization of α<inf>2</inf>-adrenergic receptors. The arylamine carboxamides differ in the number of carbon atoms separating the reactive phenyl moiety from the fused ring structure of the parent compound, rauwolscine carboxylate. Competitive inhibition studies with [<sup>3</sup>H]rauwolscine in rat kidney membranes indicate that the affinity for the carboxamide derivatives is inversely related to the length of the carbon spacer arm with rauwolscine 4-aminophenyl carboxamide (zero carbon spacer arm; rau-AMPC) exhibiting the highest affinity (K<inf>d</inf> = 2.3 ± 0.2 nM). Radioiodination of rau-AMPC yields a ligand, <inf>125</inf>I-rau-AMPC, which binds to rat kidney α<inf>2</inf>-adrenergic receptors with high affinity, as determined by both kinetic analysis (K<inf>d</inf> = k<inf>2</inf>/k<inf>1</inf> = 0.016 min<sup>-1</sup>/2.1 × 10<sup>-7</sup> min <sup>-1</sup>= 0.76 nM) and equilibrium binding studies (K<inf>d</inf> = 0.78 ± 0.16 nM). 125Irau-AMPC was quantitatively converted to the photolabile arylazide derivative 17α-hydroxy-20ayohimban-16β-(N-4-azido-3-[<sup>125</sup>I]iodophenyl)carboxamide (<sup>125</sup>I-rau-AZPC). In a partially purified receptor preparation from porcine brain, this compound photolabels a major (M<inf>r</inf> = 62,000) peptide. The labeling of this peptide is inhibited by adrenergic agonists and antagonists with a rank order of potency consistent with an a<inf>2</inf>-adrenergic receptor binding site. Both <sup>125</sup>I-rau-AMPC and the photolabile arylazide derivative, <sup>l25</sup>I-rau-AZPC, should prove useful as molecular probes for the structural and biochemical characterization of α<inf>2</inf>-adrenergic receptors.

Original languageEnglish (US)
Pages (from-to)III-120-III-124
Issue number6, Part 2
StatePublished - 1987
Externally publishedYes


  • Photoaffinity label
  • Porcine brain
  • Rauwolscine
  • α<inf>2</inf>-adrenergic receptors

ASJC Scopus subject areas

  • Internal Medicine


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