Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist1

Acta Pharmacol Sin. 2008 Oct;29(10):1187-94. doi: 10.1111/j.1745-7254.2008.00859.x.

Abstract

Aim: To screen beta2-adrenergic receptor (beta2-AR) agonists from Radix Aconiti Lateralis Preparata (RALP) as potential drug leads for asthma using a sensitive cell-based agonist assay.

Methods: The beta2-AR gene was stably expressed by Chinese hamster ovary (CHO) cells also stably expressing a cyclic adenosine monophosphate (AMP) response element-linked enhanced green fluorescent protein reporter gene. The cells were used to screen agonists from high-performance liquid chromatographic fractions of an extract of RALP. The fraction with the highest activity was selected for further compound isolation and the study of the structure-activity relationship. Its active compound was further identified by chromatography and mass spectrometry.

Results: Bioactivity-directed fractionation of the crude extract of RALP led to the isolation and characterization of the effective compound, namely hignamine. It could dose-dependently relax the isolated guinea pig trachea strip precontraction with acetylcholine with EC(50) value of (2.60+/-0.36)x10(-5) mol/L. Further in vivo studies also displayed that hignamine could protect experimental asthma model induced by histamine in guinea pigs to prolong the latent periods of asthma.

Conclusion: Hignamine, as a beta2-AR agonist existing in the extract of RALP, is the key compound contributing to the successful relief of the bronchoconstriction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aconitum / chemistry*
  • Adrenergic beta-2 Receptor Agonists
  • Adrenergic beta-Agonists / chemistry*
  • Adrenergic beta-Agonists / pharmacology*
  • Alkaloids / chemistry*
  • Alkaloids / pharmacology*
  • Animals
  • Asthma / chemically induced
  • Asthma / drug therapy
  • CHO Cells
  • Cloning, Molecular
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Histamine
  • In Vitro Techniques
  • Ligands
  • Muscle Relaxation / drug effects
  • Rats
  • Tetrahydroisoquinolines / chemistry*
  • Tetrahydroisoquinolines / pharmacology*
  • Trachea / drug effects
  • Transfection

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Adrenergic beta-Agonists
  • Alkaloids
  • Ligands
  • Tetrahydroisoquinolines
  • Histamine
  • higenamine