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 derivatives of the alpha(2)-adrenoceptor antagonist idazoxan were found to show 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 could also result in affinity and selectivity, which was moderate (2.7 nM, 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 the case of 2-(2-benzofuranyl-2-imidazoline)(2-BFI). Analogues of 2-BFI with halogenic substitutions of the aromatic ring were also found to retain 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 prove invaluable for investigating the pharmacology and physiology of I-2 receptors. Copyright (C) 1996 Elsevier Science Ltd.