Use of recombinant α₁-adrenoceptors to characterize subtype selectivity of drugs for the treatment of prostatic hypertrophy

Abstract

Several α₁-adrenoceptor antagonists have recently been developed for the treatment of benign prostatic hypertrophy because of their less frequent systemic side-effects compared to conventional α₁-adrenoceptor blockers. One potential explanation for their good tolerability would be the selectivity for a certain subtype of α₁-adrenoceptor. Utilizing COS-7 cells expressing the rat α_1A, the hamster α_1B and the human α_1C-adrenoceptors, we investigated affinities of alfuzosin, doxazisin, 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 α₁-adrenoceptor subtypes for alfuzosin (K₁ value; α_1A: 2.4 nM, α_1B: 1.4 nM, α_1C: 4.2 nM), doxazosin (K_i value; α_1A: 2.7 nM, α_1B: 3.2 nM, α_1C: 7.5 nM), terazosin (K_i value; α_1A: 2.5 nM, α_1B: 2.7 nM, α_1C: 7.1 nM), indoramin (K_i value; α_1A: 69 nM, α_1B: 21 nM, α_1C: 13 nM) and prazosin (K_i value; α_1A: 0.16 nM, α_1B: 0.19 nM, α_1C: 0.2 nM) were equipotent to the three receptor subtypes. Unlike these antagonists, both (+)- and (−)-YM617 had relatively lower affinity for α_1B receptors compared to the other subtypes (K_i value; for (+)-YM617, α_1A: 22 nM, α_1B: 96 nM, α_1C: 4.3 nM; for (−)-YM617, α_1A: 0.11 nM, α_1B: 0.7 nM, α_1C: 0.035 nM). The data suggest that α₁-adrenoceptor antagonists currently used for the treatment of the benign prostatic hyperplasia do not show substantial subtype selectivity.