IDENTIFICATION OF LIGANDS SELECTIVE FOR CENTRAL I-2-IMIDAZOLINE BINDING-SITES

Using radioligand binding techniques, several compounds selective for mammalian brain imidazoline, receptors have been identified. In rabbit brain membranes, a series of 6 and/or 7 aromatic-substituted derivati ves of the alpha(2)-adrenoceptor antagonist idazoxan were found to sho w moderate affinity for I-2 receptors over alpha(2)-adrenoceptors, in particular 6,7-dichloroidazoxan, which was 41 fold selective in favour of I-2 receptors. Modification of the benzodioxan ring of idazoxan co uld also result in affinity and selectivity, which was moderate (2.7 n M, 161 fold) in the case of the 1,3-benzodioxan isomer of idazoxan (2- (1,3-benzodioxanyl)-2-imidazoline), and high (1.3 nM, 2873 fold) in th e case of 2-(2-benzofuranyl-2-imidazoline)(2-BFI). Analogues of 2-BFI with halogenic substitutions of the aromatic ring were also found to r etain high affinity and moderate to high selectivity for I-2-sites. In particular, the 7-chloro (Ki 2.8 nM, 2192 fold) and the 4,6-dibromo ( Ki 6.1 nM, 361 fold) analogues of 2-BFI. These new ligands should prov e invaluable for investigating the pharmacology and physiology of I-2 receptors. Copyright (C) 1996 Elsevier Science Ltd.