Gasparini Fabrizio, Bilbe Graeme, Gomez-Mancilla Baltazar, Spooren Will
Novartis Pharma AG, Novartis Institutes for BioMedical Research Basel, Neurosciences Discovery, Basel, Switzerland.
Curr Opin Drug Discov Devel. 2008 Sep;11(5):655-65.
Disturbances of glutamate-mediated neurotransmission have been implicated in a broad range of nervous system disorders. Numerous attempts to correct nervous system dysfunction by pharmacological intervention at glutamate receptors have been made, and some of the approaches have achieved a high level of preclinical validation. However, in a number of cases involving agents acting as blockers of the ionotropic glutamate receptors, clinical success could not be achieved, mostly because of the lack of a therapeutic window. The identification of the metabotropic glutamate receptor (mGluR) family and their modulatory role in the control of neurotransmission provided a new means to alter glutamatergic transmission. Furthermore, selective agents acting as allosteric antagonists at the mGluR5 subtype have demonstrated therapeutic potential. The identification and characterization of mGluR5 antagonists and recent progress in clinical development are summarized.
谷氨酸介导的神经传递紊乱与多种神经系统疾病有关。人们已多次尝试通过对谷氨酸受体进行药理学干预来纠正神经系统功能障碍，其中一些方法已在临床前研究中得到高度验证。然而，在许多涉及离子型谷氨酸受体阻滞剂的案例中，未能取得临床成功，主要原因是缺乏治疗窗口。代谢型谷氨酸受体（mGluR）家族的鉴定及其在神经传递控制中的调节作用为改变谷氨酸能传递提供了新途径。此外，作为mGluR5亚型变构拮抗剂的选择性药物已显示出治疗潜力。本文总结了mGluR5拮抗剂的鉴定、特性以及临床开发的最新进展。
