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OtherAUTONOMIC PHARMACOLOGY

Actions of A-131701, a Novel, Selective Antagonist forAlpha-1A Compared with Alpha-1B Adrenoceptors on Intraurethral and Blood Pressure Responses in Conscious Dogs and a Pharmacodynamic Assessment of in Vivo Prostatic Selectivity

Arthur A. Hancock, Michael E. Brune, David G. Witte, Kennan C. Marsh, Sweta Katwala, Ivan Milicic, Lynne M. Ireland, Deanne Crowell, Michael D. Meyer and James F. Kerwin Jr.
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 628-642;
Arthur A. Hancock
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Michael E. Brune
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David G. Witte
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Kennan C. Marsh
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Sweta Katwala
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Ivan Milicic
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Lynne M. Ireland
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Deanne Crowell
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Michael D. Meyer
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Abstract

A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b, hexahydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido [3′,4′: 4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione) is a novel compound previously shown to be selective for alpha-1a sites compared with alpha-1b adrenoceptors in radioligand binding studies and isolated tissue bioassays and to block canine urethral pressure (IUP) responses to exogenous alpha-1 adrenergic agonists to a greater extent than blood pressure responses. In conscious dogs in which IUP and mean arterial blood pressure (MABP) responses were measured periodically up to 24 hr, A-131701 blocked phenylephrine (PHE)-induced increases in IUP to a greater extent than MABP responses, and the blockade of the IUP effects of PHE was significantly different from control for up to 12 hr after doses greater than 0.3 mg/kg p.o., whereas blood pressure effects were of a lesser extent and duration. In addition to the weak antagonism of PHE-induced blood pressure responses, A-131701 also exhibited minimal effects on basal blood pressure in the dog, unlike terazosin, doxazosin or tamsulosin. Pharmacokinetic analysis of plasma samples from dogs indicated that A-131701 had a half-life of 0.4 to 0.8 hr and a bioavailability of 30 to 50% in dogs. Somewhat longer half-lives were observed in rat and monkey, with bioavailability values in the 25 to 30% range. Evidence of nonlinearity of pharmacokinetics was obtained in dogs and monkeys. Pharmacodynamic analysis revealed differences between A-131701 and nonselective alpha-1 adrenoceptor antagonists in selectivity for prostatic versus vascularalpha-1 adrenoceptors based on either extent or duration of blockade, which were either similar to or superior to compounds such as tamsulosin or REC 15/2739. These data demonstrate that A-131701 selectively blocks canine prostatic alpha-1 adrenoceptors for prolonged periods compared with MABP responsesin vivo. Therefore, A-131701 should have clinical utility in the pharmacotherapy of benign prostatic hyperplasia.

Footnotes

  • Send reprint requests to: Arthur A. Hancock, Department 4 MN Building AP-10, Abbott Laboratories, Abbott Park, IL 60064.

  • Abbreviations:
    A-131701
    (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a, 4,5,9b, hexahydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido [3′,4′:4,5]thieno[3,2-d] pyrimidine-2,4(1H,3H)-dione)
    REC 15/2739
    (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2- phenyl-4H-1-benzopyran-8-carboxamide)
    PHE
    phenylephrine
    IUP
    intraurethral pressure
    MABP
    mean arterial blood pressure
    AUC
    area under the curve
    BPH
    benign prostatic hyperplasia
    t1/2
    plasma elimination half-life
    Vβ
    volume of distribution
    CLp
    plasma clearance
    Cmax
    maximal plasma concentration
    Tmax
    time to reach maximal plasma concentration
    F
    oral bioavailability
    CNS
    central nervous system
    • Received August 1, 1997.
    • Accepted November 17, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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Actions of A-131701, a Novel, Selective Antagonist forAlpha-1A Compared with Alpha-1B Adrenoceptors on Intraurethral and Blood Pressure Responses in Conscious Dogs and a Pharmacodynamic Assessment of in Vivo Prostatic Selectivity

Arthur A. Hancock, Michael E. Brune, David G. Witte, Kennan C. Marsh, Sweta Katwala, Ivan Milicic, Lynne M. Ireland, Deanne Crowell, Michael D. Meyer and James F. Kerwin
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 628-642;

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Actions of A-131701, a Novel, Selective Antagonist forAlpha-1A Compared with Alpha-1B Adrenoceptors on Intraurethral and Blood Pressure Responses in Conscious Dogs and a Pharmacodynamic Assessment of in Vivo Prostatic Selectivity

Arthur A. Hancock, Michael E. Brune, David G. Witte, Kennan C. Marsh, Sweta Katwala, Ivan Milicic, Lynne M. Ireland, Deanne Crowell, Michael D. Meyer and James F. Kerwin
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 628-642;
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