Abstract
We described herein the discovery of 1-(2-(benzo[d] [1,3]dioxol-6-yl)ethyl)-4-(2-methoxyphenyl) piperazine (LASSBio-772), as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist selected after screening of functionalized N-phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for alpha 1A and alpha 1B AR subtypes was determined through displacement of [(3)H]prazosin binding. We obtained Ki values of 0.14 nM for the alpha 1A-AR, similar to that displayed by tamsulosin (K(i) = 0.13 nM) and 5.55 nM for the alpha 1B-AR, representing a 40-fold higher affinity for alpha 1A-AR. LASSBio-772 also presented high affinity (K(B) = 0.025 nM) for the alpha 1D-AR subtype in the functional rat aorta assay, showing to be equipotent to tamsulosin (K(B) = 0.017 nM).
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic alpha-1 Receptor Antagonists / chemical synthesis*
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Adrenergic alpha-1 Receptor Antagonists / pharmacology
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Animals
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Aorta / drug effects*
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Benzodioxoles / chemical synthesis*
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Benzodioxoles / pharmacology
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Cell Membrane / drug effects*
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Cell Membrane / metabolism
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Hepatocytes / chemistry
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Liver / cytology
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Liver / drug effects
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Liver / metabolism
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Male
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Phenylephrine / pharmacology
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Piperazines / chemical synthesis*
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Piperazines / pharmacology
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Prazosin / metabolism
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Prazosin / pharmacology
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Protein Binding
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Protein Isoforms / chemistry
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Protein Isoforms / metabolism
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Rabbits
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Rats
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Receptors, Adrenergic, alpha-1 / chemistry
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Receptors, Adrenergic, alpha-1 / metabolism*
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Sulfonamides / pharmacology
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Tamsulosin
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Tissue Culture Techniques
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Tritium
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Vasoconstriction / drug effects
Substances
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1-(2-(benzo(d)(1,3)dioxol-6-yl)ethyl)-4-(2-methoxyphenyl)piperazine
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Adrenergic alpha-1 Receptor Antagonists
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Benzodioxoles
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Piperazines
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Protein Isoforms
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Receptors, Adrenergic, alpha-1
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Sulfonamides
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Tritium
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Phenylephrine
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Tamsulosin
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Prazosin