title: Use of recombinant alpha 1-adrenoceptors to characterize subtype selectivity of drugs for the treatment of prostatic hypertrophy.
abstract: Several alpha 1-adrenoceptor antagonists have recently been developed for the treatment of benign prostatic hypertrophy because of their less frequent systemic side-effects compared to conventional alpha 1-adrenoceptor blockers. One potential explanation for their good tolerability would be the selectivity for a certain subtype of alpha 1-adrenoceptor. Utilizing COS-7 cells expressing the rat alpha 1A, the hamster alpha 1B and the human alpha 1C-adrenoceptors, we investigated affinities of alfuzosin, doxazosin, terazosin, indoramin and (+)- and (-)-5-[2-[[2-(o-ethoxyphenoxy)ethyl] amino]propyl]-2-methoxybenzesulfonamide HCl (YM 617) compared to prazosin. Radioligand binding studies showed that the affinities of alpha 1-adrenoceptor subtypes for alfuzosin (Ki value; alpha 1A: 2.4 nM, alpha 1B:1.4 nM, alpha 1C:4.2 nM), doxazosin (Ki value; alpha 1A:2.7 nM, alpha 1B:3.2 nM, alpha 1C:7.5 nM), terazosin (Ki value; alpha 1A:2.5 nM, alpha 1B:2.7 nM, alpha 1C:7.1 nM), indoramin (Ki value; alpha 1A:69 nM, alpha 1B:21 nM, alpha 1C:13 nM) and prazosin (Ki value; alpha 1A:0.16 nM, alpha 1B:0.19 nM, alpha 1C:0.2 nM) were equipotent to the three receptor subtypes. Unlike these antagonists, both (+)- and (-)-YM617 had relatively lower affinity for alpha 1B receptors compared to the other subtypes (Ki value; for (+)-YM617, alpha 1A:22 nM, alpha 1B:96 nM, alpha 1C:4.3 nM; for (-)-YM617, alpha 1A:0.11 nM, alpha 1B:0.7 nM, alpha 1C:0.035 nM). The data suggest that alpha 1-adrenoceptor antagonists currently used for the treatment of the benign prostatic hyperplasia do not show substantial subtype selectivity.
authors.affiliation: Department of Molecular and Cellular Pharmacology, National Children's Medical Research Center, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Foglar
authors.forename: K
authors.initials: K
authors.lastname: Shibata
authors.forename: K
authors.initials: K
authors.lastname: Horie
authors.forename: A
authors.initials: A
authors.lastname: Hirasawa
authors.forename: G
authors.initials: G
authors.lastname: Tsujimoto
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D008297:Male; D010627:Phenethylamines / Q000378:metabolism; D010957:Plasmids; D011470:Prostatic Hyperplasia / Q000188:drug therapy*; D011869:Radioligand Assay; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D044024:Tetralones; D014162:Transfection
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D010627:Phenethylamines; D011994:Recombinant Proteins; D044024:Tetralones; C010652:BE 2254; D004247:DNA