Novel selective compounds for the investigation of imidazoline receptors

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 K(i) of 2.1 nM. BU226 (2-(4,5-dihydroimidaz-2-yl)-isoquinoline) demonstrated slightly higher affinity (K(i) 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.