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首页> 外文期刊>Journal of Medicinal Chemistry >Agonist selectivity of mGluR1 and mGluR2 metabotropic receptors: a different environment but similar recognition of an extended glutamate conformation.
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Agonist selectivity of mGluR1 and mGluR2 metabotropic receptors: a different environment but similar recognition of an extended glutamate conformation.

机译：mGluR1和mGluR2促代谢受体的激动剂选择性：不同的环境，但对扩展的谷氨酸构象的识别类似。

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摘要

To investigate the structural requirements for selective activation or blockade of metabotropic glutamate receptors, we developed a pharmacophore model for group I (mGluR1) and group II (mGluR2) agonists. The Apex-3D program was used with a training set of known active, inactive, and/or selective compounds with a wide structural diversity. The pharmacophore models were then validated by testing a set of additional known agonists. We also used competitive antagonist superpositions in order to define more precisely the topology of the mGluR1 and mGluR2 agonists' recognition site. Both models account for the activity of most potent compounds and show that the selectivity between mGluR1 and mGluR2 subtypes may be due to excluded volumes and additional binding sites, while the relative spatial position of functional groups (NH2, alpha- and gamma-CO2H) remains very similar. On both models glutamate lies in an extended form. An additional binding site is disclosed on mGluR1, while this region would be forbidden on mGluR2. This new site combines a closed and an open model for mGluR1 and accounts for the increased affinity of quisqualic acid. The models show another large hydrophobic region which is tolerated for mGluR2 and restricted for mGluR1.
机译：为了研究对代谢型谷氨酸受体的选择性激活或阻断的结构要求，我们开发了I组（mGluR1）和II组（mGluR2）激动剂的药效团模型。 Apex-3D程序与一组具有广泛结构多样性的已知活性，非活性和/或选择性化合物一起使用。然后通过测试一组其他已知的激动剂来验证药效团模型。我们还使用竞争性拮抗剂叠加，以更精确地定义mGluR1和mGluR2激动剂的识别位点的拓扑。两种模型都说明了大多数有效化合物的活性，并表明mGluR1和mGluR2亚型之间的选择性可能是由于排除了体积和附加的结合位点，而官能团（NH2，α-和γ-CO2H）的相对空间位置仍然存在非常相似。在这两种模型上，谷氨酸都处于延伸形式。在mGluR1上公开了另一个结合位点，而在mGluR2上将禁止该区域。这个新站点结合了mGluR1的封闭模型和开放模型，并说明了芥酸的亲和力增加。模型显示了另一个较大的疏水区域，该区域对mGluR2具有耐受性，而对mGluR1具有限制性。

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