In vitro and in vivo effect of BU99006 (5-isothiocyanato-2-benzofuranyl-2-imidazoline) on I₂ binding in relation to MAO: Evidence for two distinct I₂ binding sites

详细信息	查看全文 | 推荐本文 |

• 作者：Louise M. Paterson ; Robin J. Tyacke ; Emma S.J. Robinson ; David J. Nutt ; Alan L. Hudson
• 关键词：Imidazoline binding site ; Monoamine oxidase ; MAO ; BU99006 ; 2BFI ; Autoradiography ; I₂
• 刊名：Neuropharmacology
• 出版年：2007
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：February 2007
• 卷：52
• 期：2
• 页码：395-404
• 文件大小：448 K

摘要

BU99006 is an irreversible I₂ ligand which selectively inactivates I₂ binding sites, making it an ideal tool with which to study I₂ site mechanism. We sought to determine the effects of BU99006 on I₂ binding in relation to monoamine oxidase (MAO), and the time course of these effects. In vitro, rat brain membranes that were pre-treated with 10 μM BU99006 showed no change in MAO activity, despite suffering a significant reduction in [³H]2BFI binding (52.5 ± 19.6 to 8.5 ± 3.8 fmol mg⁻¹, 84%). Furthermore, reversible I₂ ligands 2BFI and BU224 were able to inhibit MAO, whether treated with BU99006 or not. In vivo, a 5 mg kg⁻¹ i.v. dose of BU99006 in rats rapidly reduced [³H]2BFI binding with similar magnitude (85%, maximal reduction after 20 min), without effect on either MAO activity or the specific binding of selective MAO-A and MAO-B radioligands. Moreover, following this irreversible treatment, recovery of central [³H]2BFI binding occurred with a rapid half-life of 4.3 h in rat brain (2.0 h in mouse), which is not consistent with a site on MAO. These data indicate that the high affinity site which is occupied by [³H]2BFI and irreversibly binds BU99006, is not the same as that which causes inhibition of MAO, and may point to the existence of another I₂ binding site.