Lavreysen Hilde, Dautzenberg Frank M
CNS Psychiatry, Janssen Pharmaceutica, a division of Johnson and Johnson Pharmaceutical Research and Development, 2340 Beerse, Belgium.
Curr Med Chem. 2008;15(7):671-84. doi: 10.2174/092986708783885246.
Metabotropic glutamate (mGlu) receptors have received much attention, driven by a strong belief in the potential of these modulatory glutamate receptors as drug targets. So far, major drug discovery programs have largely focused on group I (mGlu1 and 5) and II (mGlu2 and 3) mGlu receptors, which have been implicated in neuropathological and various psychiatric disorders. The four group III representatives (mGlu4, mGlu6, mGlu7 and mGlu8) are less understood, mainly due to the paucity of specific compounds. Recent advances in the identification of selective or specific compounds, and the generation of transgenic animals have, however, revealed important insights into the potential role of group III receptors in the pathophysiology of neurological and mood disorders. Activation of the mGlu4 receptor seems to be beneficial for treating Parkinson-like symptoms and a potential role in the treatment of mood disorders is slowly growing. Similarly, genetic inactivation studies and usage of relatively selective agonists strongly support the involvement of the mGlu8 receptor for anxiety disorders. In contrast, controversial data have been obtained for the mGlu7 receptor. While mGlu7 receptor-deficient animals show an anxiolytic profile in several in vivo readouts, the first selective allosteric agonist AMN082 has also been reported to improve anxiety-like behaviour despite activating the stress axis. The least investigated receptor remains the mGlu6 receptor, which is mostly based on its predominant expression in the retina.
代谢型谷氨酸（mGlu）受体备受关注，这源于人们坚信这些调节性谷氨酸受体具有作为药物靶点的潜力。到目前为止，主要的药物研发项目大多集中在I组（mGlu1和5）和II组（mGlu2和3）mGlu受体上，这些受体与神经病理学和各种精神疾病有关。III组的四个代表受体（mGlu4、mGlu6、mGlu7和mGlu8）则了解较少，主要是因为缺乏特异性化合物。然而，在选择性或特异性化合物的鉴定以及转基因动物的培育方面取得的最新进展，揭示了III组受体在神经和情绪障碍病理生理学中潜在作用的重要见解。mGlu4受体的激活似乎对治疗帕金森样症状有益，并且其在情绪障碍治疗中的潜在作用也在逐渐显现。同样，基因失活研究和相对选择性激动剂的使用有力地支持了mGlu8受体与焦虑症有关。相比之下，关于mGlu7受体的数据存在争议。虽然mGlu7受体缺陷动物在几种体内检测中表现出抗焦虑特征，但据报道，第一种选择性变构激动剂AMN082尽管激活了应激轴，但也能改善焦虑样行为。研究最少的受体仍然是mGlu6受体，这主要是基于其在视网膜中的主要表达。
