title: Tissue selectivity of KMD-3213, an alpha(1)-adrenoreceptor antagonist, in human prostate and vasculature.
abstract: OBJECTIVE
  We evaluated the binding and functional affinity of KMD-3213 and other alpha 1-adrenoceptor (AR) antagonists such as prazosin or tamsulosin, to compare the tissue selectivity of these antagonists between human prostate and vasculature.
  
  
  METHODS
  In the binding experiments, saturation experiments using [3H]-KMD and [3H]-prazosin (PZ) were performed, and competition of [3H]-PZ binding by antagonists was also examined in human prostatic and aortic membranes. In the functional study, contractile responses to noradrenaline were evaluated in human prostate and mesenteric artery.
  
  
  RESULTS
  [3H]-PZ bound to human prostatic and aortic membranes with subnanomolar affinity. [3H]-KMD also bound to human prostate, with higher affinity than [3H]-PZ; whereas it did not bind sufficiently to human aorta. Competition of [3H]-PZ binding revealed that KMD-3213 had more than 200-fold higher affinity for human prostate than for aorta. Binding profiles of antagonists revealed that human prostate predominantly expressed alpha 1A-AR, whereas human aorta expressed alpha 1B-AR mainly. In functional experiments, KMD-3213 potently inhibited the noradrenaline-induced contraction in human prostate as potently as tamsulosin, although prazosin showed relatively low affinity. Comparing these functional affinities with those in the mesenteric artery, only KMD-3213 exhibited substantial tissue selectivity, showing more than 100-fold higher affinity for human prostate than for mesenteric artery. Functional affinity of each antagonist suggested that noradrenaline-induced contractions were mainly mediated by alpha 1L-AR in the human prostate and by alpha 1B-AR in the mesenteric artery.
  
  
  CONCLUSIONS
  These results suggest that KMD-3213 is a substantially prostate-selective alpha 1-AR antagonist in human tissues compared with other alpha 1-AR antagonists.
authors.affiliation: Departments of Pharmacology and Urology, School of Medicine, Fukui Medical University, Matsuoka, Fukui, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Murata
authors.forename: T
authors.initials: T
authors.lastname: Taniguchi
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: K
authors.initials: K
authors.lastname: Akiyama
authors.forename: I
authors.initials: I
authors.lastname: Muramatsu
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000378:metabolism*; D001011:Aorta / Q000378:metabolism; D001667:Binding, Competitive; D001808:Blood Vessels / Q000378:metabolism*; D046508:Culture Techniques; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D011224:Prazosin / Q000378:metabolism; D011467:Prostate / Q000378:metabolism*; D011869:Radioligand Assay; D013449:Sulfonamides / Q000378:metabolism; D000077409:Tamsulosin
chemical_list: D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D013449:Sulfonamides; C095285:silodosin; D000077409:Tamsulosin; D011224:Prazosin