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Research ArticleCELLULAR AND MOLECULAR

In Vivo Demonstration of α1A-Adrenoceptor Subtype Selectivity of KMD-3213 in Rat Tissues

Shizuo Yamada, Takashi Okura and Ryohei Kimura
Journal of Pharmacology and Experimental Therapeutics January 2001, 296 (1) 160-167;
Shizuo Yamada
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Takashi Okura
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Ryohei Kimura
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Abstract

The present study was undertaken to characterize the in vivo α1-adrenoceptor binding of KMD-3213, a novel selective antagonist of α1A-adrenoceptors, in rat tissues by using a tritiated ligand with high specific activity, in comparison with that of [3H]prazosin. A significant degree of in vivo specific binding of [3H]KMD-3213 after i.v. injection of the radioligand (1.4 nmol/kg) was seen in most rat tissues, except the cerebral cortex, spleen, and liver, which showed a little or no specific binding. There was a notable difference among tissues in the time course of specific [3H]KMD-3213 binding after i.v. injection of the ligand. The specific binding in the lung, kidney, and spleen was greatest at 10 min and declined rapidly with the disappearance of the ligand from the plasma. On the other hand, [3H]KMD-3213 binding in the submaxillary gland, vas deferens, and prostate attained peak levels at 60 min, and a considerable degree of binding was present even at 240 min. After i.v. injection of a similar dose (1.2 nmol/kg) of [3H]prazosin in rats, the in vivo specific binding in the submaxillary gland was greatest at 10 min and then it fell rapidly, whereas [3H]prazosin binding in the spleen attained a peak level at 60 min, and this was maintained even at 120 min. The AUC0–120 values of the specific binding for [3H]KMD-3213, compared with those of [3H]prazosin, were markedly lower in the rat aorta, spleen, and liver, whereas the prostate, submaxillary gland, and lung showed significantly higher AUC0–120 values of [3H]KMD-3213 compared with [3H]prazosin. Furthermore, the in vivo specific binding of [3H]KMD-3213 at dose ranges of 1.4 to 13.6 nmol/kg increased linearly in the prostate and submaxillary gland, but did not increase in a dose-dependent manner in the spleen. On the other hand, there was a dose-dependent increase in the in vivo specific binding of [3H]prazosin at doses of 1.2 to 10.6 nmol/kg in all tissues. The in vivo specific binding of [3H]KMD-3213 in rat tissues was reduced by concomitant i.v. injection of low doses of prazosin in a dose-dependent manner, but not by even a relatively high dose of yohimbine. In conclusion, the present study shows that KMD-3213 binds to the α1A-adrenoceptor subtype with a higher affinity than to the α1B- and α1D- subtypes under in vivo condition, thus leading to prostate selectivity.

Footnotes

  • Send reprint requests to: Shizuo Yamada, Ph.D., Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. E-mail:yamada{at}ys7.u-shizuoka-ken.ac.jp

  • Abbreviations:
    BPH
    benign prostatic hyperplasia
    HPLC
    high pressure liquid chromatography
    Kd
    apparent dissociation constant
    Bmax
    maximum number of binding sites
    Ki
    inhibition constant
    AUC
    area under the curve
    • Received July 5, 2000.
    • Accepted September 16, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 1
1 Jan 2001
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Research ArticleCELLULAR AND MOLECULAR

In Vivo Demonstration of α1A-Adrenoceptor Subtype Selectivity of KMD-3213 in Rat Tissues

Shizuo Yamada, Takashi Okura and Ryohei Kimura
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 160-167;

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Research ArticleCELLULAR AND MOLECULAR

In Vivo Demonstration of α1A-Adrenoceptor Subtype Selectivity of KMD-3213 in Rat Tissues

Shizuo Yamada, Takashi Okura and Ryohei Kimura
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 160-167;
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