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Novel Selective Compounds for the Investigation of Imidazoline Receptors a
Author(s) -
HUDSON A. L.,
GOUGH R.,
TYACKE R.,
LIONE L.,
LALIES M.,
LEWIS J.,
HUSBANDS S.,
KNIGHT P.,
MURRAY F.,
HUTSON P.,
NUTT D. J.
Publication year - 1999
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1999.tb09344.x
Subject(s) - imidazoline receptor , receptor , chemistry , striatum , stereochemistry , binding site , dopamine , pharmacology , medicine , endocrinology , biochemistry , biology
Over several years our group has sought to synthesize and identify selective ligands for imidazoline (I) receptors, in particular the I 2 binding site. As a consequence, [ 3 H]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 I 1 and I 2 binding sites. BU224 (2‐(4,5‐dihydroimidaz‐2‐yl)‐quinoline) shows high affinity for I 2 receptors with a K i of 2.1 nM. BU226 (2‐(4,5‐dihydroimidaz‐2‐yl)‐isoquinoline) demonstrated slightly higher affinity (K i 1.4 nM) for I 2 receptors, but overall BU224 displayed greater selectivity for I 2 over I 1 receptors (832‐fold) than BU226 (380‐fold). Both compounds showed low (μM) affinity for α 2 ‐adrenoceptors. Given BU224's ability to cross the blood brain barrier, we predict that its in vivo effects are likely to be mediated via I 2 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.