PHENYLGLYCINE DERIVATIVES DISCRIMINATE BETWEEN MGLUR1-MEDIATED AND MGLUR5-MEDIATED RESPONSES
PHENYLGLYCINE DERIVATIVES DISCRIMINATE BETWEEN MGLUR1-MEDIATED AND MGLUR5-MEDIATED RESPONSES
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DOI：
10.1016/0028-3908(95)00079-l
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发表时间：
1995-08-01
影响因子：
4.7
通讯作者：
PIN, JP
中科院分区：
文献类型：
--
作者：
BRABET, I;MARY, S;PIN, JP
测试了苯甘氨酸衍生物α-甲基-4-羧基苯甘氨酸（MCPG）、4-羧基苯甘氨酸（4CPG）、4-羧基-3-羟基苯甘氨酸（4C 3 HPG）、3-羟基苯甘氨酸（3 HPG）和3，4-二氢苯甘氨酸（DHPG）对瞬时表达大鼠mGluRla或mGluR 5a受体的LLC-PK 1细胞的作用。如其他人先前报道的，发现（S）-3HPG和（RS）-DHPG是mGluR la的部分激动剂，而（+）-MCPG、（S）-4CPG和（S）-4C3HPG竞争性地拮抗Glu的作用。令人惊讶的是，苯甘氨酸的4-羧基衍生物拮抗1 S，3R-ACPD对mGluR 1a的作用，K-B值较低。在mGluRSa上，（S）-3HPG和（RS）-DHPG也是部分激动剂。但与其对mGluR 1a的作用相反，（S）-4CPG不抑制Glu或1 S，3R-ACPD的作用，而（S）-4C3HPG在高浓度下起激动剂作用。尽管用1 mM（+）-MCPG未观察到Glu对mGluRSa作用的显著拮抗作用，但发现该化合物可有效和竞争性拮抗1 S，3R-ACPD的作用。最后，4CPG的效果也进行了检查，分别表达mGluR 5和mGluR 1 mRNA的培养皮层和小脑神经元。4CPG仅抑制1 S，3R-ACPD刺激的小脑神经元IP产生。这些结果（1）表明苯甘氨酸衍生物可用于区分mGluR 1和mGluR 5介导的效应，（2）表明苯甘氨酸拮抗剂的表观效力取决于用于激活这些受体的激动剂。
The effects of the phenylglycine derivatives, alpha-methyl-4-carboxyphenylglycine (MCPG), 4-carboxyphenylglycine (4CPG), 4-carboxy-3-hydroxyphenylglycine (4C3HPG), 3-hydroxyphenylglycine (3HPG) and 3,4-dihydrohyphenylglycine (DHPG) were tested on LLC-PK1 cells transiently expressing the rat mGluRla or mGluR5a receptors. As previously reported by others, (S)-3HPG and (RS)-DHPG were found to be partial agonists at mGluR la, whereas (+)-MCPG, (S)-4CPG and (S)-4C3HPG competitively antagonized the effect of Glu. Surprisingly, the 4-carboxy derivatives of phenylglycine antagonized the effect of 1S,3R-ACPD on mGluR1a with lower K-B values. On mGluRSa, (S)-3HPG and (RS)-DHPG are also partial agonists. However, in contrast to their effects on mGluR1a, (S)-4CPG did not inhibit the effect of Glu or 1S,3R-ACPD, and (S)-4C3HPG acted as an agonist at high concentration. Whereas no significant antagonism of the Glu effect on mGluRSa was observed with 1 mM(+)-MCPG, this compound was found to potently and competitively antagonize the effect of 1S,3R-ACPD. Finally, the effect of 4CPG was also examined on cultured cortical and cerebellar neurons that express mGluR5 and mGluR1 mRNA, respectively. 4CPG inhibited 1S,3R-ACPD stimulated IP production in cerebellar neurons only. These results (1) demonstrate that phenylglycine derivatives can be used to discriminate between effects mediated by mGluR1 and mGluR5 and (2) suggest that the apparent potency of phenylglycine antagonists depends on the agonist used to activate these receptors.