Pharmacology of (S)-homoquisqualic acid and (S)-2-amino-5-phosphonopentanoic acid [(S)-AP5] at cloned metabotropic glutamate receptors
Pharmacology of (S)-homoquisqualic acid and (S)-2-amino-5-phosphonopentanoic acid [(S)-AP5] at cloned metabotropic glutamate receptors
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DOI：
10.1038/sj.bjp.0701616
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发表时间：
1998-01-01
影响因子：
7.3
通讯作者：
Krogsgaard-Larsen, P
中科院分区：
文献类型：
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作者：
Bräuner-Osborne, H;Krogsgaard-Larsen, P
1本研究分别测定了（S）-使君子酸、（S）-2-氨基-4-膦酰基丁酸（（S）-AP 4）及其高级同系物（S）-高使君子酸、（S）-2-氨基-5-膦酰基戊酸（（S）-AP 5）的药理学特征，2（S）-使君子酸是一种有效的mGlu（1）/mGlu（5）受体激动剂（EC 50值为1.1 μ M和0.055 μ M，3（S）-高使君子酸对mGlu（1）显示竞争性拮抗作用，（K-B=184 μ M）和在mGlu（5）下的完全激动作用（EC 50 =36 μ M）和mGlu（2）（EC_（50）=23 μ M），但对mGlu（4）无活性。4（S）-AP_4是一种有效的选择性mGlu（4）激动剂（EC 50 =0.91 μ M）对mGlu（1）、mGlu和mGlu（5）作为激动剂和拮抗剂均无活性。5（S）-AP 5对mGlu（4）显示非常弱的激动剂活性。在mGlu（2）受体亚型（S）-AP 5作为竞争性拮抗剂（K-B=205 μ M），而该化合物对mGlu（1）和mGlu（5）无活性。（R）-AP 5对作为激动剂和拮抗剂测试的所有mGlu受体亚型均无活性。6这些研究表明，在（S）谷氨酸及其类似物的骨架中掺入额外的碳原子以产生相应的同系物，以及用电子等排酸性基团取代末端羧基对mGlu受体亚型的药理学特征具有深远影响。此外，（S）-高使君子酸已被证明是区分mGlu（1）和mGlu（5）的潜在有用工具。
1 In this study we have determined the pharmacological profile of (S)-quisqualic acid, (S)-2-amino-4-phosphonobutyric acid ((S)-AP4) and their higher homologues (S)-homoquisqualic acid, (S)-2-amino-5-phosphonopentanoic acid ((S)-AP5), respectively, and (R)-AP5 at subtypes of metabotropic (S)-glutamic acid (mGlu) receptors expressed in Chinese hamster ovary cells.2 (S)-Quisqualic acid was a potent mGlu(1)/mGlu(5) agonist (EC50 values of 1.1 mu M and 0.055 mu M, respectively) showing no activity at mGlu(2) and weak agonism at mGlu(4) (EC(50)similar to 1000 mu M).3 (S)-Homoquisqualic acid displayed competitive antagonism at mGlu(1) (K-B=184 mu M) and full agonism at mGlu(5) (EC50=36 mu M) and mGlu(2) (EC50=23 mu M), but was inactive at mGlu(4).4 (S)-AP4 was a potent and selective mGlu(4) agonist (EC50=0.91 mu M) being inactive at mGlu(1), mGlu, and mGlu(5) both as agonist and antagonist.5 (S)-AP5 displayed very weak agonist activity at mGlu(4). At the mGlu(2) receptor subtype (S)-AP5 acted as a competitive antagonist (K-B=205 mu M), whereas the compound was inactive at mGlu(1) and mGlu(5). (R)-AP5 was inactive at all mGlu receptor subtypes tested both as agonist and antagonist.6 These studies demonstrate that incorporation of an additional carbon atom into the backbone of (S)glutamic acid and its analogues, to give the corresponding homologues, and replacement of the terminal carboxyl groups by isosteric acidic groups have profound effects on the pharmacological profiles at mGlu receptor subtypes. Furthermore, (S)-homoquisqualic acid has been shown to be a potentially useful tool for differentiating mGlu(1) and mGlu(5).