T-0156, a novel phosphodiesterase type 5 inhibitor, and sildenafil have different pharmacological effects on penile tumescence and electroretinogram in dogs

Eur J Pharmacol. 2004 Feb 6;485(1-3):283-8. doi: 10.1016/j.ejphar.2003.11.052.

Abstract

T-0156 (2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride) is a newly synthesized phosphodiesterase type 5 inhibitor, and its potency and selectivity are higher than those of sildenafil in an enzyme assay. In the present study with anesthetized dogs, we examined the effects of intravenous T-0156 or sildenafil on the pelvic nerve stimulation-induced penile tumescence and light-adapted flicker stimulation-induced electroretinogram, parameters of which are reported to be indicators for inhibition of phosphodiesterase type 5 and type 6, respectively. Both compounds potentiated the penile tumescence in a dose-dependent manner. T-0156 at 10 microg/kg and sildenafil at 100 microg/kg showed almost the same potentiating percentage (181.5+/-31.1% and 190.0+/-37.9%) in spite of the plasma concentration of T-0156 being about five times lower than that of sildenafil (16.7+/-1.6 and 78.8+/-5.3 ng/ml), indicating that the effect of T-0156 on tumescence is more potent than that of sildenafil. While the high dose of T-0156 (1000 microg/kg) reduced the amplitude and increased the latency of the electroretinogram positive wave, the effects of T-0156 were conversely weaker than those of sildenafil (reduction of amplitude; T-0156: 41.1+/-8.0%, sildenafil: 71.7+/-3.9%, increase of latency; T-0156: 3.9+/-0.6%, sildenafil: 14.5+/-1.4%, at 1000 microg/kg). These results clearly showed the difference in the properties of T-0156 and sildenafil in pharmacological studies with anesthetized dogs, and the difference appeared to correspond with their inhibitory potencies for phosphodiesterase type 5 and type 6. It was concluded that T-0156 would be a useful pharmacological tool as a potent and highly selective phosphodiesterase type 5 inhibitor.

Publication types

  • Comparative Study

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dogs
  • Dose-Response Relationship, Drug
  • Electroretinography / methods
  • Male
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology*
  • Penile Erection / drug effects*
  • Penile Erection / physiology
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Photic Stimulation / methods
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Purines
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Retina / drug effects*
  • Retina / enzymology
  • Retina / physiology
  • Sildenafil Citrate
  • Sulfones

Substances

  • Naphthyridines
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Purines
  • Pyrimidines
  • Sulfones
  • T0156
  • Sildenafil Citrate
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5