Z-350, a new chimera compound possessing alpha1-adrenoceptor antagonistic and steroid 5alpha-reductase inhibitory actions

Naunyn Schmiedebergs Arch Pharmacol. 1999 Jun;359(6):433-8. doi: 10.1007/pl00005372.

Abstract

The effects of Z-350, (S)-4-[3-(4-{1-(4-methyl-phenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy} benzoyl)indole-1-yl]butyric acid hydrochloride, a newly synthesized compound possessing alpha-adrenoceptor antagonistic and steroid 5alpha-reductase inhibitory actions, were studied in vitro. In functional experiments, Z-350 shifted the concentration/response curve for the phenylephrine-induced contraction of rabbit prostate, urethra and aorta to the right with pA2 values of 8.04, 7.57 and 7.13, respectively. The binding affinity of Z-350 for alpha1-adrenoceptors in rabbit prostate, urethra and aorta were estimated by the displacement of [3H]prazosin. The pKi values for this action of Z-350 were 7.53, 7.95 and 7.62 for the prostate, urethra and aorta, respectively. alpha1-Adrenoceptor subtype selectivities were studied in the submaxillary gland (r(1A) and liver (alpha1B) of rat. Z-350 inhibited the specific binding of [3H]prazosin to alpha1A and (alpha1B-adrenoceptors with pKi values of 7.82 and 7.29, respectively. Z-350 inhibited rat prostatic steroid 5alpha-reductase non-competitively with a pIC50 of 8.42. These results indicate that Z-350 is a alpha1-adrenoceptor antagonist and is a steroid 5alpha-reductase inhibitor. It is expected that Z-350 will be a candidate drug for the treatment of benign prostatic hyperplasia.

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism
  • 5-alpha Reductase Inhibitors*
  • Adrenergic alpha-1 Receptor Antagonists*
  • Adrenergic alpha-Agonists / pharmacology
  • Adrenergic alpha-Antagonists / pharmacology*
  • Animals
  • Aorta, Thoracic / drug effects
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • In Vitro Techniques
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Male
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Phenylephrine / pharmacology
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Prostate / drug effects
  • Rabbits
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Urethra / drug effects

Substances

  • 5-alpha Reductase Inhibitors
  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Enzyme Inhibitors
  • Indoles
  • Piperazines
  • Receptors, Adrenergic, alpha-1
  • Z 350
  • Phenylephrine
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase