Synthesis and adrenergic activity of a new series of N-aryl dicyclopropyl ketone oxime ethers: SAR and stereochemical aspects

J Med Chem. 1998 May 7;41(10):1613-8. doi: 10.1021/jm970338c.

Abstract

A novel series of 31 N-aryl dicyclopropyl ketone oxime ethers were synthesized and tested for their activity at alpha- and beta-adrenergic receptors. All of the compounds showed greater affinity for beta-than for alpha1-receptor sites. Some compounds had pure antagonist effects whereas some were partial agonists. Several compounds had an antagonist effect matching that of propranolol in in vitro (binding data and pA2 values on rat heart ventricle homogenates and guinea pig spontaneously beating right and electrically driven left atrial isolated preparations, respectively) and in in vivo tests (measurement of antagonism toward isoprenaline-induced tachycardia in anesthetized rats). Furthermore, all of the compounds showed a beta1-adrenergic selectivity (beta2-affinity > 1500 nM).

Publication types

  • Comparative Study

MeSH terms

  • Adrenergic Agonists / chemical synthesis
  • Adrenergic Agonists / chemistry
  • Adrenergic Agonists / metabolism
  • Adrenergic Agonists / pharmacology
  • Adrenergic beta-Antagonists* / chemical synthesis
  • Adrenergic beta-Antagonists* / chemistry
  • Adrenergic beta-Antagonists* / metabolism
  • Adrenergic beta-Antagonists* / pharmacology
  • Animals
  • Cyclopropanes* / chemical synthesis
  • Cyclopropanes* / chemistry
  • Cyclopropanes* / metabolism
  • Cyclopropanes* / pharmacology
  • Guinea Pigs
  • Heart Rate / drug effects
  • In Vitro Techniques
  • Ligands
  • Male
  • Myocardial Contraction / drug effects
  • Optical Rotation
  • Oximes* / chemical synthesis
  • Oximes* / chemistry
  • Oximes* / metabolism
  • Oximes* / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, alpha-1 / drug effects
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / metabolism*
  • Receptors, Adrenergic, beta-1 / drug effects
  • Receptors, Adrenergic, beta-1 / metabolism
  • Receptors, Adrenergic, beta-2 / drug effects
  • Receptors, Adrenergic, beta-2 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Adrenergic Agonists
  • Adrenergic beta-Antagonists
  • Cyclopropanes
  • Ligands
  • Oximes
  • Receptors, Adrenergic, alpha-1
  • Receptors, Adrenergic, beta
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2