Synthesis and characterization of arylamine derivatives of rauwolscine as molecular probes for α2-adrenergic receptors

S. M. Lanier, R. M. Graham, H. J. Hess, A. Grodski, M. G. Repaske, J. M. Nunnari, L. E. Limbird, C. J. Homcy

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The selective α2-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 α2-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 [3H]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(d) = 2.3 ± 0.2 nM). Radioiodination of rau-AMPC yields a ligand, 125I-rau-AMPC, which binds to rat kidney α2-adrenergic receptors with high affinity, as determined by both kinetic analysis (K(d) = k2/k1 = 0.016 min-1/2.1 x 107 M-1 min-1 = 0.76 nM) and equilibrium binding studies (K(d) = 0.78 ± 0.16 nM). 125I-rau-AMPC was quantitatively converted to the photolabile arylazide derivative 17α-hydroxy-20α-yohimban-16β-(N-4-azido-3- [125I]iodophenyl)carboxamide (125I-rau-AZPC). In a partially purified receptor preparation from porcine brain, this compound photolabels a major (M(r) = 62,000) peptide. The labeling of this peptide is inhibited by adrenergic agonists and antagonists with a rank order of potency consistent with an α2-adrenergic receptor binding site. Both 125I-rau-AMPC and the photolabile arylazide derivative, 125I-rau-AZPC, should prove useful as molecular probes for the structural and biochemical characterization of α2-adrenergic receptors.

Original languageEnglish (US)
Issue number6 II SUPPL.
StatePublished - 1987
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine


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