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Novel Selective Compounds for the Investigation of Imidazoline Receptorsa

Authors

  • A. L. HUDSON,

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  • R. GOUGH,

    1. Psychopharmacology Unit, School of Medical Sciences. University Walk, University of Bristol, Bristol, BS8 1TD, UK
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  • R. TYACKE,

    1. Psychopharmacology Unit, School of Medical Sciences. University Walk, University of Bristol, Bristol, BS8 1TD, UK
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  • L. LIONE,

    1. Psychopharmacology Unit, School of Medical Sciences. University Walk, University of Bristol, Bristol, BS8 1TD, UK
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  • M. LALIES,

    1. Psychopharmacology Unit, School of Medical Sciences. University Walk, University of Bristol, Bristol, BS8 1TD, UK
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  • J. LEWIS,

    1. Psychopharmacology Unit, School of Medical Sciences. University Walk, University of Bristol, Bristol, BS8 1TD, UK
    2. Department of Organic Chemistry, University of Bristol, Cantocks Close, Bristol, BS8 1TS, UK
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  • S. HUSBANDS,

    1. Psychopharmacology Unit, School of Medical Sciences. University Walk, University of Bristol, Bristol, BS8 1TD, UK
    2. Department of Organic Chemistry, University of Bristol, Cantocks Close, Bristol, BS8 1TS, UK
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  • P. KNIGHT,

    1. Psychopharmacology Unit, School of Medical Sciences. University Walk, University of Bristol, Bristol, BS8 1TD, UK
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  • F. MURRAY,

    1. Psychopharmacology Unit, School of Medical Sciences. University Walk, University of Bristol, Bristol, BS8 1TD, UK
    2. Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK
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  • P. HUTSON,

    1. Psychopharmacology Unit, School of Medical Sciences. University Walk, University of Bristol, Bristol, BS8 1TD, UK
    2. Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK
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  • D. J. NUTT

    1. Psychopharmacology Unit, School of Medical Sciences. University Walk, University of Bristol, Bristol, BS8 1TD, UK
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  • a

    We thank the Wellcome Trust for their generous financial support.

Author for correspondence: Alan Hudson, e-mail, a.l.hudson@bris.ac.uk; phone, 0117 9288608; fax, 0117 9277057.

Abstract

ABSTRACT: Over several years our group has sought to synthesize and identify selective ligands for imidazoline (I) receptors, in particular the I2 binding site. As a consequence, [3H]2-(2-benzofuranyl)-2-imidazoline (2BFI) has proved extremely useful for binding and autoradiographic studies. More recently we have synthesized a BU series of compounds and examined these for their affinities for both I1 and I2 binding sites. BU224 (2-(4,5-dihydroimidaz-2-yl)-quinoline) shows high affinity for I2 receptors with a Ki of 2.1 nM. BU226 (2-(4,5-dihydroimidaz-2-yl)-isoquinoline) demonstrated slightly higher affinity (Ki 1.4 nM) for I2 receptors, but overall BU224 displayed greater selectivity for I2 over I1 receptors (832-fold) than BU226 (380-fold). Both compounds showed low (μM) affinity for α2-adrenoceptors. Given BU224's ability to cross the blood brain barrier, we predict that its in vivo effects are likely to be mediated via I2 receptors. Brain dialysis revealed BU224 to dose dependently (0–20 mg/kg ip) elevate basal noradrenaline in rat frontal cortex and basal dopamine in striatum. In a rat model of opiate withdrawal, behavioral studies showed that BU224 (10 mg/kg, sc) was able to reduce acute weight loss and diarrhea, but not the number of wet dog shakes associated with the withdrawal syndrome.

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