USE OF RECOMBINANT ALPHA(1)-ADRENOCEPTORS TO CHARACTERIZE SUBTYPE SELECTIVITY OF DRUGS FOR THE TREATMENT OF PROSTATIC HYPERTROPHY

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 a 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(1A)-adrenoceptor subtypes for alfuzosin (K-i value; alpha(1A): 2.4 nM, alpha(1B):1.4 nM, alpha(1C):4.2 nM), doxazosin (K-i value; alpha(1A): 2.7 nM, alpha(1B): 3.2 nM, alpha(1C): 7.5 nM), terazosin (K-i value; alpha(1A): 2.5 nM, alpha(1B): 2.7 nM, alpha(1C): 7.1 nM), indoramin (K-i value; alpha 1A: 69 nM, alpha(1B): 21 nM, alpha(1C): 13 nM)) and prazosin (K-i 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 ct,, receptors compared to the other subtypes (K-i 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 a,-adrenoceptor antagonists currently used for the treatment of the benign prostatic hyperplasia do not show substantial subtype selectivity.