Tamsulosin potently and selectively antagonizes human recombinant α(1A/1D)-adrenoceptors: slow dissociation from the α(1A)-adrenoceptor may account for selectivity for α(1A)-adrenoceptor over α(1B)-adrenoceptor subtype.
We determined the binding affinity of tamsulosin, a selective α(1)-adrenoceptor antagonist, for human α(1)-adrenoceptor subtypes in comparison with those of other α(1)-adrenoceptor antagonists including silodosin, prazosin, 5-methylurapidil, terazosin, alfuzosin, nafopidil, urapidil and BMY7378. The association and dissociation kinetics of [(3)H]tamsulosin for recombinant human α(1)-adrenoceptor subtypes were compared with those of [(3)H]prazosin. Tamsulosin competitively inhibited [(3)H]prazosin binding to human α(1A)-, α(1B)- and α(1D)-adrenoceptors (pK(i) values were 10.38, 9.33, 9.85) indicating 11 and 3.4-fold higher affinities for human α(1A)-adrenoceptor than those for α(1B)- and α(1D)-adrenoceptors, respectively. The affinity of tamsulosin for the human α(1A)-adrenoceptor was, respectively, 5, 9.9, 38, 120, 280, 400, 1200 and 10000 fold higher than those of silodosin, prazosin, 5-methylurapidil, terazosin, alfuzosin, naftopidil, urapidil and BMY7378, respectively. [(3)H]Tamsulosin dissociated from the α(1A)-adrenoceptor slower than from the α(1B)- and α(1D)-adrenoceptors (α(1B)>α(1D)>α(1A)). Moreover, [(3)H]tamsulosin dissociated slower than [(3)H]prazosin from the α(1A)-adrenoceptor and faster from the α(1B)- and α(1D)-adrenoceptors. In conclusion, tamsulosin potently and selectively antagonized α(1A/1D)-adrenoceptor ligand binding, and slowly dissociated from the α(1A)-adrenoceptor subtype.
Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc, Miyukigaoka, Tsukuba, Ibaraki 305–8585, Japan. shuichi.sato@jp.astellas.com
Shuichi
S
Sato
Toshiki
T
Hatanaka
Hironori
H
Yuyama
Masashi
M
Ukai
Yukiko
Y
Noguchi
Akiyoshi
A
Ohtake
Katsunari
K
Taguchi
Masao
M
Sasamata
Keiji
K
Miyata
D058668:Adrenergic alpha-1 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001667:Binding, Competitive; D006801:Humans; D007700:Kinetics; D008297:Male; D011470:Prostatic Hyperplasia / Q000188:drug therapy*; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry*; D011994:Recombinant Proteins; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000077409:Tamsulosin
D058668:Adrenergic alpha-1 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D011994:Recombinant Proteins; D013449:Sulfonamides; D000077409:Tamsulosin