作为红藻氨酸受体拮抗剂的威拉地丁衍生物的合成与药理学

Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors.

作者信息

Dolman Nigel P, Troop Helen M, More Julia C A, Alt Andrew, Knauss Jody L, Nistico Robert, Jack Samantha, Morley Richard M, Bortolotto Zuner A, Roberts Peter J, Bleakman David, Collingridge Graham L, Jane David E

机构信息

Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, University of Bristol, Bristol, BS8 1TD, UK.

出版信息

J Med Chem. 2005 Dec 1;48(24):7867-81. doi: 10.1021/jm050584l.

DOI:10.1021/jm050584l

PMID:16302825

Abstract

The natural product willardiine (8) is an AMPA receptor agonist while 5-iodowillardiine (10) is a selective kainate receptor agonist. In an attempt to produce antagonists of kainate and AMPA receptors analogues of willardiine with substituents at the N3 position of the uracil ring were synthesized. The N3-4-carboxybenzyl substituted analogue (38c) was found to be equipotent at AMPA and GLUK5-containing kainate receptors in the neonatal rat spinal cord. The N3-2-carboxybenzyl substituted analogue (38a) proved to be a potent and selective GLUK5 subunit containing kainate receptor antagonist when tested on native rat and human recombinant AMPA and kainate receptor subtypes. The GLUK5 kainate receptor antagonist activity was found to reside in the S enantiomer (44a) whereas the R enantiomer (44b) was almost inactive. 5-Iodo substitution of the uracil ring of 44a gave 45, which was found to have enhanced potency and selectivity for GLUK5.

摘要

天然产物怀尔地碱（8）是一种AMPA受体激动剂，而5-碘代怀尔地碱（10）是一种选择性海人藻酸受体激动剂。为了制备海人藻酸和AMPA受体的拮抗剂，合成了在尿嘧啶环N3位带有取代基的怀尔地碱类似物。发现N3-4-羧基苄基取代类似物（38c）在新生大鼠脊髓的AMPA受体和含GLUK5的海人藻酸受体上具有同等效力。当在天然大鼠和人重组AMPA及海人藻酸受体亚型上进行测试时，N3-2-羧基苄基取代类似物（38a）被证明是一种强效且选择性的含GLUK5亚基的海人藻酸受体拮抗剂。发现GLUK5海人藻酸受体拮抗剂活性存在于S对映体（44a）中，而R对映体（44b）几乎无活性。44a的尿嘧啶环进行5-碘取代得到45，发现其对GLUK5具有增强的效力和选择性。