A novel, competitive mGlu5 receptor antagonist (LY344545) blocks DHPG-induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices
A novel, competitive mGlu5 receptor antagonist (LY344545) blocks DHPG-induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices
复制标题
DOI：
10.1038/sj.bjp.0703574
复制
发表时间：
2000-09-01
影响因子：
7.3
通讯作者：
Collingridge, GL
中科院分区：
文献类型：
--
作者：
Doherty, AJ;Palmer, MJ;Collingridge, GL
1 我们研究了 LY344545 的药理学特性，LY344545 是广谱竞争性代谢型谷氨酸受体拮抗剂 LY341495 的结构相关差向异构体。我们发现 LY344545 还竞争性拮抗几乎所有 mGlu 受体亚型，但具有广谱活性。人受体亚型的效力顺序为 mGlu(5a)（IC50 为 5.5 +/- 0.6 μM）> mGlu(2) = mGlu(3) > mGlu(1 α) = mGlu(7) > mGlu(6) = mGlu(8)。在最高使用浓度（100 μM）下未检测到显着的 mGlu(4) 受体拮抗剂活性。 100 μM LY344545 在放射性配体结合测定中置换了 50+/-5% 的 [H-3]-CGP39653 结合，但小于 30% 的 [H-3]-红藻氨酸或 [H-3]-AMPA。2 LY344545 以浓度依赖性方式拮抗 mGlu 受体转染的 CHO 细胞中 L-谷氨酸刺激的 Ca2+ 释放，10与大鼠mGlu1α受体(K-i=20.5+/-2.1μM)相比，对大鼠mGlu(5a)受体(K-i=2.1+/-0.6μM)的亲和力高倍。 50 μM (1S, 3R)-ACPD 诱导的海马 CA1 神经元 Ca2+ 升高也被拮抗 (IC50 = 6.8+/-0.7 μM)。3 LY344545 拮抗 10 μM (S)-3,5-DHPG 诱导的 CAI 神经元 NMDA 去极化增强 (EC50=10.6+/-1.0 μM)。米）。在较高浓度（大于或等于 100 μM）下，LY344545 是一种 NMDA 受体拮抗剂。4 LY344545 还阻断 CA3 至 CA1 突触处 LTP 的诱导，但不阻断其表达，IC50 > 300 μM。这种效应与其对 NMDA 受体的弱活性一致。5 这些结果表明，配体与 mGlu 受体亚型的结合严重依赖于给定化学药效团内相同分子取代基的空间取向。 LY344545 被鉴定为第一个对 mGlu(5) 受体表现出选择性的竞争性拮抗剂，这支持了设计该受体更具选择性和更有效的竞争性拮抗剂的潜力。6这些结果进一步表明，mGlu 受体介导的 NMDA 反应增强对于诱导 LTP 并不是必需的。
1 We have investigated the pharmacological properties of LY344545, a structurally related epimer of the broad spectrum competitive metabotropic glutamate receptor antagonist, LY341495. We have found that LY344545 also antagonizes competitively nearly all mGlu receptor subtypes, but with a wide spectrum of activity. The order of potency for the human receptor isoforms was mGlu(5a) (IC50 of 5.5 +/- 0.6 mu M) > mGlu(2) = mGlu(3) > mGlu(1 alpha) = mGlu(7) > mGlu(6) = mGlu(8). No significant mGlu(4) receptor antagonist activity was detected at the highest concentration used (100 mu M). 100 mu M LY344545 displaced 50+/-5% of [H-3]-CGP39653 binding, but less than 30% of [H-3]-kainate or [H-3]-AMPA in radioligand binding assays.2 LY344545 antagonized L-glutamate stimulated Ca2+ release in CHO cells transfected with mGlu receptors in a concentration dependent manner with a 10 fold higher affinity for the rat mGlu(5a) receptor (K-i=2.1+/-0.6 mu M) compared to the rat mGlu1 alpha receptor (K-i=20.5+/-2.1 mu M). 50 mu M (1S, 3R)-ACPD-induced Ca2+ rises in hippocampal CA1 neurones were also antagonized (IC50 = 6.8+/-0.7 mu M).3 LY344545 antagonized 10 mu M (S)-3,5-DHPG-induced potentiation of NMDA depolarizations in CAI neurones (EC50=10.6+/-1.0 mu M). At higher concentrations (greater than or equal to 100 mu M), LY344545 was an NMDA receptor antagonist.4 LY344545 also blocked the induction, but not the expression, of LTP at CA3 to CA1 synapses with an IC50 > 300 mu M. This effect is consistent with its weak activity at NMDA receptors.5 These results demonstrate that the binding of ligands to mGlu receptor subtypes is critically dependent on the spatial orientation of the same molecular substituents within a given chemical pharmacophore. The identification of LY344545 as the first competitive antagonist to show selectivity towards mGlu(5) receptors supports the potential to design more selective and potent competitive antagonists of this receptor.6 These results further indicate that mGlu receptor-mediated potentiation of NMDA responses is not essential for the induction of LTP.