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Research ArticleNEUROPHARMACOLOGY

An Investigation of the Uroselective Properties of Four Novel α1a-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
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 224-229;
Virginia L. Pulito
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Xiaobing Li
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Sally S. Varga
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Linda S. Mulcahy
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Kerry S. Clark
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Sheridan A. Halbert
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Allen B. Reitz
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William V. Murray
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Linda K. Jolliffe
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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

  • 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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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleNEUROPHARMACOLOGY

An Investigation of the Uroselective Properties of Four Novel α1a-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
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 224-229;

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Research ArticleNEUROPHARMACOLOGY

An Investigation of the Uroselective Properties of Four Novel α1a-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
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 224-229;
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