Pinkerton Anthony B, Vernier Jean-Michel, Schaffhauser Hervé, Rowe Blake A, Campbell Una C, Rodriguez Dana E, Lorrain Daniel S, Baccei Christopher S, Daggett Lorrie P, Bristow Linda J
Merck Research Laboratories-San Diego, 3535 General Atomics Court, San Diego, California 92121, USA.
J Med Chem. 2004 Aug 26;47(18):4595-9. doi: 10.1021/jm040088h.
Herein we disclose the discovery of a new class of positive allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2), phenyl-tetrazolyl acetophenones, e.g. 1-(2-hydroxy-3-propyl-4-[4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy]phenyl) ethanone (4). These potentiators were shown to have no effect in the absence of glutamate as well as no effect at mGlu3 or the other mGlu receptors. The compounds were also evaluated in rodent models with potential relevance for schizophrenia, and 4 was shown to have activity in the inhibition of ketamine-induced norepinephrine release and ketamine-induced hyperactivity. This represents the first example of the efficacy of mGlu2 receptor potentiators in these models.
在此，我们披露了一类新的代谢型谷氨酸受体2（mGlu2）的正变构增强剂——苯基四唑基苯乙酮的发现，例如1-(2-羟基-3-丙基-4-[4-[4-(2H-四唑-5-基)苯氧基]丁氧基]苯基)乙酮（4）。这些增强剂在无谷氨酸的情况下显示无作用，并且对mGlu3或其他mGlu受体也无作用。这些化合物还在与精神分裂症潜在相关的啮齿动物模型中进行了评估，结果显示4具有抑制氯胺酮诱导的去甲肾上腺素释放和氯胺酮诱导的多动的活性。这代表了mGlu2受体增强剂在这些模型中有效性的首个实例。
