Synthesis and biological profile of the enantiomers of [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-cis-octahydroquinoxalin- 1-yl]furan-2-ylmethanone (cyclazosin), a potent competitive alpha 1B- adrenoceptor antagonist

J Med Chem. 1996 Nov 8;39(23):4602-7. doi: 10.1021/jm960510x.


The enantiomers of [4-(4-amino-6, 7-dimethoxyquinazolin-2-yl)-cis-octahydroquinoxalin-1-yl]-fu ran- 2-ylmethanone (cyclazosin, 1) were synthesized from the chiral furan-2-yl(cis-octahydroquinoxalin-1-yl)methanone [(+)-2 and (-)-2], which were obtained by resolution of the racemic amine with (S)-(+)- and (R)-(-)-mandelic acid. The binding profile of the enantiomers of 1 was assessed at alpha 1-, alpha 2-, D2, and 5-HT1A receptors as well as at native alpha 1A- and alpha 1B- and cloned alpha 1a-, alpha 1b-, and alpha 1d-adrenoceptor subtypes in comparison with prazosin, spiperone, and AH11110A. (+)-1 displayed a 40-90-fold selectivity for the alpha 1B(alpha 1b)-adrenoceptor relative to alpha 1A(alpha 1a) and alpha 1d subtypes. A significant enantioselectivity was observed at the alpha 1A(alpha 1a)-adrenoceptor and particularly at alpha 1d-adrenoceptors since (-)-1 was 11-14- and 47-fold, respectively, more potent than (+)-1. Furthermore the enantiomer (+)-1 displayed selectivities of 1100-, 19000-, and 12000-fold in binding to alpha 1b-adrenoceptors relative to alpha 2-adrenoceptors and 5-HT1A and D2 receptors. These results indicate that (+)-1, [(+)-cyclazosin] is the most potent and selective ligand for the alpha 1B-adrenoceptor subtype so far described and may be a valuable tool in the characterization of alpha 1-adrenoceptor subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists*
  • Adrenergic alpha-Antagonists / chemical synthesis*
  • Adrenergic alpha-Antagonists / chemistry
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Binding Sites
  • CHO Cells
  • COS Cells
  • Cattle
  • Cerebral Cortex / metabolism
  • Cricetinae
  • Humans
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Male
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Quinoxalines / chemical synthesis*
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Stereoisomerism


  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Antagonists
  • Quinazolines
  • Quinoxalines
  • Receptors, Adrenergic, alpha-1
  • cyclazosin