Synthesis, beta-adrenergic blocking activity and beta-receptor binding affinities of 1-substituted-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalates

Farmaco. 2003 Aug;58(8):557-62. doi: 10.1016/s0014-827x(03)00083-1.

Abstract

The compounds 1-isopropylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate (5) and 1-tert-butylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate (6) were synthesized from thymol (1), a naturally occurring agent in Thymus vulgaris L. Pharmacological evaluation of 5 and 6 were carried out using mouse ECG and isolated rat uterus models. Pretreatment of 5 (100 microg/kg, i.v.) and 6 (50 microg/kg, i.v.) antagonized isoprenaline (2 microg/kg, i.v.) induced tachycardia, similar to that of atenolol (CAS 29122-68-7, 20 microg/kg, i.v.) pretreatment in mouse ECG experiments as measured by R-R interval. Pretreatment of 5 and 6 blocked isoprenaline and adrenaline induced relaxation of isolated rat uterus (unprimed). Also the compounds 5 and 6 were subjected to in vitro beta1- and beta2-adrenergic receptor binding assay using turkey erythrocyte membrane (beta1) and lung homogenate of rats (beta2). Both 5 and 6 showed beta-adrenergic receptor affinity comparable with that of propranolol (propranolol hydrochloride, CAS 318-98-9) with out selectivity to any one beta-adrenergic receptor. These results suggest that both the compounds possess non-selective beta-adrenergic blocking activity, with the tert-butyl derivative 6 being more active than the isopropyl derivative 5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Antagonists*
  • Adrenergic beta-2 Receptor Antagonists*
  • Adrenergic beta-Antagonists / chemical synthesis*
  • Adrenergic beta-Antagonists / metabolism
  • Adrenergic beta-Antagonists / pharmacology*
  • Animals
  • Atenolol / pharmacology
  • Binding, Competitive
  • Electrocardiography / drug effects
  • Erythrocyte Membrane / drug effects
  • Erythrocyte Membrane / metabolism
  • Female
  • Heart Rate / drug effects
  • Isoproterenol / pharmacology
  • Male
  • Mice
  • Oxalates / chemical synthesis*
  • Oxalates / metabolism
  • Oxalates / pharmacology*
  • Propanols / chemical synthesis
  • Propanols / metabolism
  • Propanols / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, beta-1 / metabolism
  • Receptors, Adrenergic, beta-2 / metabolism
  • Thymol / chemistry
  • Thymus Plant / chemistry
  • Uterus / drug effects

Substances

  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-2 Receptor Antagonists
  • Adrenergic beta-Antagonists
  • Oxalates
  • Propanols
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Thymol
  • Atenolol
  • Isoproterenol