Brabet I, Parmentier M L, De Colle C, Bockaert J, Acher F, Pin J P
Centre INSERM-CNRS de Pharmacologie-Endocrinologie, UPR 9023-CNRS, Montpellier, France.
Neuropharmacology. 1998 Aug;37(8):1043-51. doi: 10.1016/s0028-3908(98)00091-4.
In a previous study we reported that the addition of a carboxylic group to the mGlu receptor agonist aminocyclopentane-1,3-dicarboxylate (ACPD) changes its properties from agonist to antagonist at both mGlu1 and mGlu2 receptors, and resulted in an increase in affinity at mGlu4 receptors, with isomers being either agonists or antagonists. In the present study, the effect of gamma-carboxy-L-glutamic acid (Gla) and (2S,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), two carboxylic derivatives of non-selective agonists, were examined on all cloned mGlu receptors. We found that this additional carboxylic group on glutamate prevents its interaction with group-I mGlu receptors and generates a potent group-II antagonist (K(B) = 55 microM on mGlu2). At group-III mGlu receptors, Gla was found to be either an antagonist (mGlu7 and mGlu8 receptors) or a partial agonist (mGlu4 and mGlu6 receptors). We show here that L-CCG-I is a general mGlu receptor agonist activating all cloned receptors. We also confirm that DCG-IV, which corresponds to L-CCG-I with an additional carboxylic group, is a selective group-II agonist. However, this additional COOH group changes the properties of L-CCG-I from an agonist to an antagonist at all group-III receptors, making this compound one of the most potent group-III mGlu receptor antagonist known so far. These observations will be useful for the development of more potent and selective mGlu receptor agonists and antagonists.
在之前的一项研究中，我们报道了向代谢型谷氨酸受体（mGlu）激动剂氨基环戊烷-1,3-二羧酸（ACPD）中添加一个羧基，会使其在mGlu1和mGlu2受体上的性质从激动剂转变为拮抗剂，并导致其对mGlu4受体的亲和力增加，其异构体既有激动剂也有拮抗剂。在本研究中，我们检测了两种非选择性激动剂的羧基衍生物——γ-羧基-L-谷氨酸（Gla）和（2S,2'R,3'R）-2-（2,3-二羧基环丙基）甘氨酸（DCG-IV）对所有克隆的mGlu受体的作用。我们发现，谷氨酸上的这个额外羧基会阻止其与I组mGlu受体相互作用，并产生一种强效的II组拮抗剂（对mGlu2的K(B) = 55 μM）。在III组mGlu受体上，Gla被发现要么是拮抗剂（mGlu7和mGlu8受体），要么是部分激动剂（mGlu4和mGlu6受体）。我们在此表明，L-CCG-I是一种能激活所有克隆受体的通用mGlu受体激动剂。我们还证实，与L-CCG-I相比多了一个羧基的DCG-IV是一种选择性II组激动剂。然而，这个额外的COOH基团使L-CCG-I在所有III组受体上的性质从激动剂转变为拮抗剂，使该化合物成为迄今为止已知的最强效的III组mGlu受体拮抗剂之一。这些观察结果将有助于开发更有效、更具选择性的mGlu受体激动剂和拮抗剂。
