Enzymological and pharmacological profile of T-0156, a potent and selective phosphodiesterase type 5 inhibitor

Eur J Pharmacol. 2002 Dec 5;456(1-3):91-8. doi: 10.1016/s0014-2999(02)02590-6.


The enzymological and pharmacological properties of 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 (T-0156), a new phosphodiesterase type 5 inhibitor, were studied in vitro and in vivo. The inhibitory effects of T-0156 on six phosphodiesterase isozymes isolated from canine tissues were investigated. T-0156 specifically inhibited the hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase type 5, at low concentration (IC(50)=0.23 nM), in a competitive manner. T-0156 also inhibited phosphodiesterase type 6 with IC(50) value of 56 nM, which was 240-fold higher than that for inhibition of phosphodiesterase type 5. T-0156 had low potencies against phosphodiesterase types 1, 2, 3, and 4 (IC(50)>10 microM). In the isolated rabbit corpus cavernosum, T-0156 at 10 and 100 nM increased cGMP levels (100 nM T-0156-treated: 6.0+/-1.5 pmol/mg protein, vehicle-treated: 1.1+/-0.4 pmol/mg protein, P<0.05), causing relaxation of the tissue. T-0156 at 1 to 100 nM potentiated the electrical field stimulation-induced relaxation in the isolated rabbit corpus cavernosum in a concentration-dependent manner (100 nM T-0156-treated: 76.9+/-19.8%, vehicle-treated: 12.3+/-10.1%, P<0.05). Intraduodenal administration of T-0156 at 100 to 1000 microg/kg potentiated the pelvic nerve stimulation-induced tumescence in anesthetized dogs (1000 microg/kg T-0156-treated: 279.0+/-38.4%, vehicle-treated: 9.8+/-4.5%, P<0.05). These results suggested that T-0156 enhanced the nitric oxide (NO)/cGMP pathway, probably through blockade of phosphodiesterase type 5 in vitro and in vivo experimental conditions. The present study clearly showed that T-0156 is a potent and highly selective phosphodiesterase type 5 inhibitor, which is a useful tool for pharmacological studies in vitro and in vivo.

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Anesthesia
  • Animals
  • Binding, Competitive / drug effects
  • Cyclic GMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dogs
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • In Vitro Techniques
  • Isoenzymes / drug effects
  • Isoenzymes / metabolism
  • Kinetics
  • Male
  • Muscle Contraction / drug effects
  • Naphthyridines / pharmacology*
  • Penile Erection / drug effects
  • Penis / drug effects
  • Penis / metabolism
  • Penis / physiology
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / drug effects
  • Phosphoric Diester Hydrolases / metabolism*
  • Pyrimidines / pharmacology*
  • Rabbits
  • Radioligand Assay


  • Isoenzymes
  • Naphthyridines
  • Phosphodiesterase Inhibitors
  • Pyrimidines
  • T0156
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cyclic GMP