Effects of tamsulosin metabolites at alpha-1 adrenoceptor subtypes.
We have investigated the affinity and selectivity of tamsulosin and its metabolites, M1, M2, M3, M4 and AM1, at the tissue and the cloned alpha-1 adrenoceptor subtypes in the radioligand binding and the functional studies. In the radioligand binding studies, the compounds competed for [3H]prazosin binding to the rat liver and kidney alpha-1 adrenoceptors, with the rank order of potency tamsulosin approximately M4 > M1 > M2 approximately M3 > > AM1 with the latter having a negligible affinity. All compounds differentiated cloned alpha-1 adrenoceptor subtypes with the rank order of potency of alpha-1A > or = alpha-1D > alpha-1B, except for M4 which had the highest affinity for the alpha-1D adrenoceptor. The compounds also concentration-dependently antagonized phenylephrine-induced contractions in the rabbit aorta and prostate. The resulting apparent pA2 values were very similar to those at the cloned rat alpha-1A adrenoceptor. We conclude that most tamsulosin metabolites are high potency antagonists at the alpha-1 adrenoceptors and retain the alpha-1A over the alpha-1B adrenoceptor selectivity of tamsulosin.
Taguchi
K
K
Department of Medicine, University of Essen, Germany.
Saitoh
M
M
Sato
S
S
Asano
M
M
Michel
M C
MC
D000317:Adrenergic alpha-Antagonists / Q000378:metabolism*; D000818:Animals; D008297:Male; D011224:Prazosin / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism*; D000077409:Tamsulosin
D000317:Adrenergic alpha-Antagonists; D018340:Receptors, Adrenergic, alpha-1; D011994:Recombinant Proteins; D013449:Sulfonamides; D000077409:Tamsulosin; D011224:Prazosin