title: Pharmacological characterization of TA-0201, an endothelin receptor antagonist, with recombinant and human prostate endothelin receptors.
abstract: The pharmacological profile of N-(6-(2-(5-bromopyrimidine-2-yloxy)ethoxy)-5-(4-methylphenyl)pyrimidin-4-yl)-4-(2-hydroxy-1,1-dimethylethyl) benzensulfonamide sodium salt sesquihydrate (TA-0201), a new antagonist of endothelin receptors, was examined, using human recombinant and prostate endothelin receptors. In binding experiments with [125I]endothelin-1, TA-0201 showed extremely high affinity for recombinant endothelin ET(A) receptors (pK(i)=10.7), as compared with that for recombinant endothelin ET(B) receptors (pK(i)=7.8). Endothelin ET(A) and ET(B) receptors coexisted in human prostate with different proportions (endothelin ET(A) receptor: approximately 70%), which were distinguished by TA-0201 in the same manner as with recombinant receptors. Human prostate strips contracted in response to endothelin-1 and sorafotoxin S6c, but the maximum contraction induced by endothelin-1 was approximately three times greater than that induced by sarafotoxin S6c. The response to endothelin-1, but not to sarafotoxin S6c, was inhibited by TA-0201 and cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ123) (endothelin ET(A) receptor antagonist) but not by BQ788 (endothelin ET(B) receptor antagonist). These results suggest that TA-0201 is a highly selective endothelin ET(A) receptor antagonist and will be useful for understanding the physiological and pathological roles of the endothelin ET(A) receptor in human prostate and other tissues.
authors.affiliation: Department of Pharmacology, School of Medicine, Fukui Medical University, Matsuoka, Fukui 910-1193, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takanobu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanamaru
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Okada
authors.forename: Ikunobu
authors.initials: I
authors.lastname: Muramatsu
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D011869:Radioligand Assay; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000819:agonists / Q000378:metabolism; D017466:Receptors, Endothelin / Q000819:agonists / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology*; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D011994:Recombinant Proteins; D013449:Sulfonamides; C113972:T 0201; D014757:Viper Venoms; C057354:sarafotoxins s6