Alkylating beta-blockers: activity of isomeric bromoacetyl alprenolol menthanes

J Med Chem. 1985 Nov;28(11):1699-703. doi: 10.1021/jm00149a028.


An affinity label for beta-adrenoceptors, N-(bromoacetyl)-N'-[3-(o-allylphenoxy)-2-hydroxypropyl]-1,8-dia min o-p-menthane, has been extensively used in the form of a mixture of four isomers. In the present study, all four isomers were isolated, their structures elucidated, and their interactions with beta-adrenoceptors characterized. The isomer with the aromatic (pharmacophore) group on carbon 1 of p-menthane and with the Z configuration (Z-1) predominates in the mixture and has the highest affinity for beta-adrenoceptors of rat heart (KD = 3 X 10(-8) M) and lungs (KD = 2 X 10(-8) M). This isomer acts as a ligand that binds irreversibly at the drug binding site of the receptor (i.e., after treatment and extensive washing of the membrane preparation, the concentration of the receptors is decreased in a dose-dependent manner), while binding characteristics of the remaining receptors are not changed. The corresponding E diastereomer (E-1) also binds irreversibly to the drug binding site of the receptor. The isomer with the aromatic group on carbon 8 and the Z configuration (Z-8) modifies the receptor noticeably only at higher concentrations and then on a site apparently different from the drug-binding site, i.e., affinity of receptors after the treatment and washing is changed. The corresponding E diastereomer (E-8) modified both the drug-binding and alternative binding site. The results suggest that there is some flexibility in the conformation of the beta-adrenoceptor that enables pairs of ligands, differing by axial or equatorial positions of critical groups, to alkylate the receptor in an analogous manner.

Publication types

  • Comparative Study

MeSH terms

  • Adrenergic beta-Antagonists / metabolism
  • Affinity Labels / metabolism
  • Alprenolol / analogs & derivatives*
  • Alprenolol / chemical synthesis
  • Alprenolol / metabolism
  • Alprenolol / pharmacology
  • Animals
  • Cell Membrane / metabolism
  • Dihydroalprenolol / metabolism
  • Isomerism
  • Lung / metabolism
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Myocardium / metabolism
  • Rats
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / metabolism*
  • Structure-Activity Relationship


  • Adrenergic beta-Antagonists
  • Affinity Labels
  • Receptors, Adrenergic, beta
  • Dihydroalprenolol
  • bromoacetylalprenololmenthane
  • Alprenolol