A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators
A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators
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代谢型谷氨酸受体亚型 1 的一类新型正性异构调节剂与一个不同于负性异构调节剂的位点相互作用
DOI：
10.1124/mol.105.021857
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发表时间：
2006-08-01
影响因子：
3.6
通讯作者：
Conn, P. Jeffrey
中科院分区：
文献类型：
--
作者：
Hemstapat, Kamondanai;de Paulis, Tomas;Conn, P. Jeffrey
我们最近报道了一类新的化合物，以3-氰- n -（1,3-二苯基- 1h -吡唑-5-基）苯酰胺（CDPPB）为代表，作为代谢性谷氨酸受体（mGluR）亚型5的正变构调节剂（增强剂）。对CDPPB类似物的研究表明，该系列中的一些化合物也可作为mGluR1的正变构调节剂。虽然CDPPB相对于其他mGluR亚型对mGluR5具有选择性，但在表达mGluR1的细胞中，几种CDPPB类似物在10 μ M时也显示出2.5倍的谷氨酸诱导钙瞬变增强，其中4-硝基-n -（1,4-二苯基- 1hpyrazol5 -酰基）苯酰胺（VU-71）对mGluR1具有选择性。在之前的研究中，我们发现两种结构类型的mGluR5选择性变构增强剂（包括CDPPB）与mGluR5变构拮抗剂2-甲基-6-（苯乙基）吡啶具有共同的结合位点。据报道，mGluR1的负变构调节剂，无论其结构类型如何，都与该受体上的一个共同变构拮抗剂位点结合。然而，无论是新的CDPPB类似物还是先前鉴定的变构mGluR1增强剂[e]。例如，(S)-2（4-氟苯基）-1-（甲苯-4-磺酰基）吡罗烷（Ro 67-7476），二苯基乙酰氨基甲酸乙酯（Ro 01-6128）和丁基（9Hxanthene9-羰基）氨基甲酸酯（Ro 67-4853）]取代了[3H] 1-（3,4-二氢- 2h -吡喃[2,3-b]喹啉-7-基）2-苯基-1-乙烷（R214127）的结合，[3H] 1-（3,4-二氢- 2h -pyrano[2,3-b]喹啉-7-基），这是mGluR1上变构拮抗剂位点的高亲和力放射性配体，其浓度比诱导mGluR1变构增强反应所需的浓度高几个量级。这些数据表明，mGluR1的变构增强剂作用于与mGluR1的变构拮抗剂不同的位点。位点定向诱变表明，mGluR1a跨膜V中757位的缬氨酸对多种类型的变构mGluR1增强剂的活性至关重要。
We recently reported a novel class of compounds, represented by 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), that act as positive allosteric modulators (potentiators) of metabotropic glutamate receptor (mGluR) subtype 5. Studies of CDPPB analogs revealed that some compounds in this series serve also as positive allosteric modulators of mGluR1. Although CDPPB is selective for mGluR5 relative to other mGluR subtypes, several CDPPB analogs also showed 2.5-fold potentiation of glutamate-induced calcium transients in cells expressing mGluR1 at 10 mu M, with 4-nitro-N-(1,4-diphenyl-1Hpyrazol5- yl) benzamide (VU-71) being selective for mGluR1. In previous studies, we found that two structural classes of mGluR5-selective allosteric potentiators, including CDPPB, share a common binding site with the allosteric mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine. Negative allosteric modulators of mGluR1, regardless of structural class, have been reported to bind to a common allosteric antagonist site on this receptor. However, neither the novel CDPPB analogs nor previously identified allosteric mGluR1 potentiators [e. g., (S)-2( 4-fluorophenyl)-1-(toluene-4-sulfonyl) pyrrolidine (Ro 67-7476), ethyl diphenylacetylcarbamate (Ro 01-6128), and butyl (9Hxanthene9- carbonyl) carbamate (Ro 67-4853)] displaced the binding of [3H] 1-(3,4-dihydro-2H-pyrano[2,3-b] quinolin-7-yl)2- phenyl-1-ethanone (R214127), a high-affinity radioligand for the allosteric antagonist site on mGluR1 at concentrations several orders of magnitude higher than those required to induce allosteric potentiation of mGluR1 responses. These data suggest that allosteric potentiators of mGluR1 act at a site that is distinct from that of allosteric antagonists of mGluR1. Sitedirected mutagenesis revealed that valine at position 757 in transmembrane V of mGluR1a is crucial for the activity of multiple classes of allosteric mGluR1 potentiators.