Hemstapat Kamondanai, de Paulis Tomas, Chen Yelin, Brady Ashley E, Grover Vandana K, Alagille David, Tamagnan Gilles D, Conn P Jeffrey
Department of Pharmacology, Vanderbilt University Medical Center, 23rd Ave. South at Pierce, 417-D Preston Research Bldg., Nashville, TN 37232-6600, USA.
Mol Pharmacol. 2006 Aug;70(2):616-26. doi: 10.1124/mol.105.021857. Epub 2006 Apr 27.
We recently reported a novel class of compounds, represented by 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CD-PPB), 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 muM, with 4-nitro-N-(1,4-diphenyl-1H-pyrazol-5-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 (9H-xanthene-9-carbonyl)carbamate (Ro 67-4853)] displaced the binding of [(3)H]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. Site-directed mutagenesis revealed that valine at position 757 in transmembrane V of mGluR1a is crucial for the activity of multiple classes of allosteric mGluR1 potentiators.
我们最近报道了一类新型化合物，以3-氰基-N-(1,3-二苯基-1H-吡唑-5-基)苯甲酰胺(CD-PPB)为代表，它作为代谢型谷氨酸受体(mGluR)亚型5的正变构调节剂(增强剂)发挥作用。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。尽管相对于其他mGluR亚型，CDPPB对mGluR5具有选择性，但几种CDPPB类似物在10 μM时也使表达mGluR1的细胞中谷氨酸诱导的钙瞬变增强了2.5倍，其中4-硝基-N-(1,4-二苯基-1H-吡唑-5-基)苯甲酰胺(VU-71)对mGluR1具有选择性。在先前的研究中，我们发现包括CDPPB在内的两类mGluR5选择性变构增强剂与变构mGluR5拮抗剂2-甲基-6-(苯乙炔基)吡啶共享一个共同的结合位点。据报道，无论结构类型如何，mGluR1的负变构调节剂都结合在该受体上一个共同的变构拮抗剂位点。然而，无论是新型CDPPB类似物还是先前鉴定的变构mGluR1增强剂[例如，(S)-2-(4-氟苯基)-1-(甲苯-4-磺酰基)吡咯烷(Ro 67-7476)、二苯基乙酰氨基甲酸乙酯(Ro 01-6128)和丁基(9H-呫吨-9-羰基)氨基甲酸酯(Ro 67-4853)]，在比诱导mGluR1反应变构增强所需浓度高几个数量级的浓度下，都不能取代[(3)H]1-(3,4-二氢-2H-吡喃并[2,3-b]喹啉-7-基)-2-苯基-1-乙酮(R214127)的结合，R214127是mGluR1上变构拮抗剂位点的高亲和力放射性配体。这些数据表明，mGluR1的变构增强剂作用于一个与mGluR1变构拮抗剂不同的位点。定点诱变显示，mGluR1a跨膜区V中第757位的缬氨酸对多类变构mGluR1增强剂的活性至关重要。
