An investigation of the uroselective properties of four novel alpha(1a)-adrenergic receptor subtype-selective antagonists

The development of alpha(1a)-adrenergic receptor (AR) subtype-selective ant agonists is likely to result in uroselective agents that effectively treat benign prostatic hyperplasia (BPH) symptoms without causing undesirable sid e effects that may be due to vascular alpha(1)-AR blockade. The properties of four aryl piperazine compounds (RWJ-38063, RWJ-68141, RWJ-68157, and RWJ -69736) are described in this report and compared with the properties of ta msulosin, an alpha(1)-AR antagonist that is used in the treatment of BPH. R adioligand binding studies show that all four RWJ compounds have significan tly higher affinity for the alpha(1a)-AR subtype than for the alpha(1b) or alpha(1d) subtype and display a higher level of receptor subtype selectivit y than tamsulosin. The RWJ compounds were more potent in inhibiting (+/-)-n orepinephrine-induced contractions of isolated rat prostate tissue than tho se of isolated rat aorta tissue, whereas tamsulosin had the reversed tissue selectivity. RWJ-38063 and RWJ-69736 had the highest potency in the isolat ed prostate tissue assays of the four RWJ compounds, with pK(B) values of 8 .24 and 9.26, respectively, and were 319- and 100-fold more potent in their effects on isolated prostate tissue than aorta tissue. The in vivo urosele ctivities of RWJ-38063, RWJ-69736, and tamsulosin were examined in anesthet ized dogs. Both RWJ compounds suppressed the intraurethral pressure respons e to phenylephrine to a greater extent than the mean arterial pressure resp onse; however, RWJ-69736 also caused a marked transient rise in heart rate. Although less potent, RWJ-38063 and RWJ-69736 were notably more uroselecti ve than tamsulosin in this canine model.