A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors
A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors
复制标题
DOI：
10.1124/jpet.106.117093
复制
发表时间：
2007-07-01
影响因子：
3.5
通讯作者：
Conn, P. Jeffrey
中科院分区：
文献类型：
--
作者：
Hemstapat, Kamondanai;Da Costa, Herve;Conn, P. Jeffrey
第二类代谢性谷氨酸受体(MGluRs)，mGluR2和mGluR3，在哺乳动物脑中发挥着重要作用，是治疗某些中枢神经系统疾病的新靶点。我们现在报道了一类新的二氢苯并[1，4]二氮杂-2-酮衍生物的合成和表征，它们是II族mGluRs的选择性负变构调节剂。这些化合物同时抑制mGluR2和mGluR3，但在I和III组mGluR没有活性。新的mGluR2/3拮抗剂还能有效地阻断mGluR2/3介导的对海马片穿通径突触的场兴奋性突触后电位的抑制。这些化合物导致谷氨酸浓度-反应关系中的最大反应向右移动，并降低最大反应，这与非竞争性拮抗作用机制一致。此外，放射性配基结合研究表明，邻位构型拮抗剂[H-3]LY341495[2S-2-氨基-2-(1S，2S-2-羧基-环丙基)-3-(黄烷-9-基)丙酸]的结合没有影响。定点突变表明，跨膜V(N735D)的单点突变对第二类mGluRs负变构调节剂的抑制活性不是关键的，它是mGluR2变构增强剂LY487379[N-(4-(2-甲氧基苯氧基)-N-(2，2-三氟乙磺酰基)吡啶-3-甲胺]的重要残基。然而，人类GluR2的这一单一突变几乎完全阻断了mGluR2的一种新的变构增强剂联苯吲哚A的增强活性。我们的数据表明，mGluR2的这两个正变构调节子可能共享一个共同的结合位点，该结合位点可能不同于第二组mGluRs的新的负变构调节子的结合位点。
Group II metabotropic glutamate receptors ( mGluRs), mGluR2 and mGluR3, play a number of important roles in mammalian brain and represent exciting new targets for certain central nervous system disorders. We now report synthesis and characterization of a novel family of derivatives of dihydrobenzo[ 1,4] diazepin-2-one that are selective negative allosteric modulators for group II mGluRs. These compounds inhibit both mGluR2 and mGluR3 but have no activity at group I and III mGluRs. The novel mGluR2/3 antagonists also potently block mGluR2/3- mediated inhibition of the field excitatory postsynaptic potentials at the perforant path synapse in hippocampal slices. These compounds induce a rightward shift and decrease the maximal response in the glutamate concentration-response relationship, consistent with a noncompetitive antagonist mechanism of action. Furthermore, radioligand binding studies revealed no effect on binding of the orthosteric antagonist [H-3] LY341495 [2S-2-amino-2-(1S, 2S-2-carboxycyclopropan1- yl)-3-( xanth-9-yl) propionic acid]. Site-directed mutagenesis revealed that a single point mutation in transmembrane V ( N735D), previously shown to be an important residue for potentiation activity of the mGluR2 allosteric potentiator LY487379 [ N-(4-(2-methoxyphenoxy) phenyl)- N-( 2,2,2- trifluoroethylsulfonyl) pyrid- 3- ylmethylamine], is not critical for the inhibitory activity of negative allosteric modulators of group II mGluRs. However, this single mutation in human GluR2 almost completely blocked the enhancing activity of biphenyl- indanone A, a novel allosteric potentiator of mGluR2. Our data suggest that these two positive allosteric modulators of mGluR2 may share a common binding site and that this site may be distinct from the binding site for the new negative allosteric modulators of group II mGluRs.