Abstract
The development of α1a-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 α1-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 α1-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 α1a-AR subtype than for the α1b or α1d 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 pKB 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.
Footnotes
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Send reprint requests to: Virginia L. Pulito, The R. W. Johnson Pharmaceutical Research Institute, Route 202, P.O. Box 300, Raritan, NJ 08869-0602. E-mail:vpulito{at}prius.jnj.com
- Abbreviations:
- BPH
- benign prostatic hyperplasia
- AR
- adrenergic receptor
- IUP
- intraurethral pressure
- MAP
- mean arterial pressure
- [125I]HEAT
- (±)-β-([125I]iodo-4-hydroxyphenyl)-1-ethyl-aminoethyl-tetralone
- NE
- (±)-norepinephrine
- Received January 18, 2000.
- Accepted March 14, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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