Vol. 294, Issue 1, 224-229, July 2000

An Investigation of the Uroselective Properties of Four Novel _1a-Adrenergic Receptor Subtype-Selective Antagonists

Virginia L. Pulito, Xiaobing Li, Sally S. Varga, Linda S. Mulcahy, Kerry S. Clark, Sheridan A. Halbert, Allen B. Reitz, William V. Murray and Linda K. Jolliffe

The R. W. Johnson Pharmaceutical Research Institute, Drug Discovery Division, Raritan, New Jersey (V.L.P., S.S.V., W.V.M., L.K.J.); The R. W. Johnson Pharmaceutical Research Institute, Drug Discovery Division, La Jolla, California (X.L.); Ortho Biotech, Inc., Corporate Development, Raritan, New Jersey (L.S.M.); BioDevelopment Associates, L.L.C., Bellevue, Washington (K.S.C., S.A.H.); and The R. W. Johnson Pharmaceutical Research Institute, Drug Discovery Division, Spring House, Pennsylvania (A.B.R.)

The development of _1a-adrenergic receptor (AR) subtype-selective antagonists is likely to result in uroselective agents that effectively treat benign prostatic hyperplasia (BPH) symptoms without causing undesirable side effects that may be due to vascular 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 tamsulosin, an ₁-AR antagonist that is used in the treatment of BPH. Radioligand binding studies show that all four RWJ compounds have significantly higher affinity for the _1a-AR subtype than for the _1b or _1d subtype and display a higher level of receptor subtype selectivity than tamsulosin. The RWJ compounds were more potent in inhibiting (±)-norepinephrine-induced contractions of isolated rat prostate tissue than those of isolated rat aorta tissue, whereas tamsulosin had the reversed tissue selectivity. RWJ-38063 and RWJ-69736 had the highest potency in the isolated 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 uroselectivities of RWJ-38063, RWJ-69736, and tamsulosin were examined in anesthetized dogs. Both RWJ compounds suppressed the intraurethral pressure response to phenylephrine to a greater extent than the mean arterial pressure response; however, RWJ-69736 also caused a marked transient rise in heart rate. Although less potent, RWJ-38063 and RWJ-69736 were notably more uroselective than tamsulosin in this canine model.