title: Identification of ligands selective for central I2-imidazoline binding sites.
abstract: Using radioligand binding techniques, several compounds selective for mammalian brain imidazoline 2 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 I2 receptors over alpha 2-adrenoceptors, in particular 6,7-dichloroidazoxan, which was 41 fold selective in favour of I2 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 I2-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 I2 receptors.
authors.affiliation: Psychopharmacology Unit, School of Medical Sciences, University of Bristol, U.K.
authors.forename: A L
authors.initials: AL
authors.lastname: Hudson
authors.forename: C B
authors.initials: CB
authors.lastname: Chapleo
authors.forename: J W
authors.initials: JW
authors.lastname: Lewis
authors.forename: S
authors.initials: S
authors.lastname: Husbands
authors.forename: K
authors.initials: K
authors.lastname: Grivas
authors.forename: N J
authors.initials: NJ
authors.lastname: Mallard
authors.forename: D J
authors.initials: DJ
authors.lastname: Nutt
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D019329:Idazoxan / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D054755:Imidazoline Receptors; D008024:Ligands; D008297:Male; D011817:Rabbits; D011869:Radioligand Assay; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C105202:6,7-dichloroidazoxan; D000317:Adrenergic alpha-Antagonists; D001572:Benzofurans; D054755:Imidazoline Receptors; D008024:Ligands; D011942:Receptors, Adrenergic, alpha; D011955:Receptors, Drug; D019329:Idazoxan