Kuhn R, Pagano A, Stoehr N, Vranesic I, Flor P J, Lingenhöhl K, Spooren W, Gentsch C, Vassout A, Pilc A, Gasparini F
Nervous System Research, Novartis, Pharma AG, Basel, Switzerland.
Amino Acids. 2002;23(1-3):207-11. doi: 10.1007/s00726-001-0130-6.
There is a need to identify subtype-specific ligands for mGlu receptors to elucidate the potential of these receptors for the treatment of nervous system disorders. To date, most mGlu receptor antagonists are amino acid-like compounds acting as competitive antagonists at the glutamate binding site located in the large extracellular N-terminal domain. We have characterized novel subtype-selective mGlu(5) receptor antagonists which are structurally unrelated to competitive mGlu receptor ligands. Using a series of chimeric receptors and point mutations we demonstrate that these antagonists act as inverse agonists with a novel allosteric binding site in the seven-transmembrane domain. Recent studies in animal models implicate mGlu(5) receptors as a potentially important therapeutic target particularly for the treatment of pain and anxiety.
有必要鉴定代谢型谷氨酸（mGlu）受体的亚型特异性配体，以阐明这些受体在治疗神经系统疾病方面的潜力。迄今为止，大多数mGlu受体拮抗剂都是氨基酸类化合物，它们在位于大的细胞外N端结构域的谷氨酸结合位点处作为竞争性拮抗剂起作用。我们已经鉴定出新型的亚型选择性mGlu(5)受体拮抗剂，其在结构上与竞争性mGlu受体配体无关。通过一系列嵌合受体和点突变，我们证明这些拮抗剂作为反向激动剂，在七跨膜结构域具有一个新的变构结合位点。最近在动物模型中的研究表明，mGlu(5)受体是一个潜在的重要治疗靶点，特别是在治疗疼痛和焦虑方面。
