Portoghese P S, Nagase H, Lipkowski A W, Larson D L, Takemori A E
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
J Med Chem. 1988 Apr;31(4):836-41. doi: 10.1021/jm00399a026.
In an effort to develop selective antagonists for kappa opioid receptors, bivalent ligands that contain opioid antagonist pharmacophores derived from naltrexone or other morphinans were synthesized and tested on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. The minimum requirements for kappa selectivity are at least one free phenolic OH group and one N-cyclopropyl or N-ally substituent. Several compounds (3, 8, 10) with kappa selectivity as good as or better than norbinaltorphimine (nor-BNI, 2) were discovered. The structure-activity relationship revealed that the pyrrole ring functions strictly as a spacer and does not contribute to kappa selectivity. The pharmacologic data suggest that only one antagonist pharmacophore may be required for kappa selectivity and that the other morphinan portion of the molecule confers selectivity by interacting with a unique subsite proximal to the antagonist pharmacophore recognition locus.
为了开发κ阿片受体的选择性拮抗剂，合成了含有源自纳曲酮或其他吗啡喃的阿片拮抗剂药效基团的二价配体，并在豚鼠回肠（GPI）和小鼠输精管（MVD）制剂上进行了测试。κ选择性的最低要求是至少一个游离酚羟基和一个N - 环丙基或N - 烯丙基取代基。发现了几种κ选择性与纳布啡诺（nor - BNI，2）相当或更好的化合物（3、8、10）。构效关系表明，吡咯环仅起间隔作用，对κ选择性无贡献。药理学数据表明，κ选择性可能仅需要一个拮抗剂药效基团，分子的另一个吗啡喃部分通过与拮抗剂药效基团识别位点附近的独特亚位点相互作用赋予选择性。
