The consensus that ketamine can produce rapid-onset antidepressant effects in patients combined with the recent approval of S(+)-ketamine (esketamine, Spravato) as an antidepressant, has fueled the search for other compounds that might recapitulate the remarkable therapeutic benefits of ketamine. At the same time, discovery efforts have been additionally directed toward minimization of the tolerability, side-effect, and safety issues associated with ketamine. The history of thought on the viability of metabotropic 2/3 (mGlu2/3) receptor antagonism as a potential mechanism for inducing rapid-acting antidepressant effects is reviewed here. The biological basis for predicting antidepressant efficacy of mGlu2/3 receptor antagonists in depressed patients is also presented. This prediction is based upon convergent biochemical, neurochemical, electrophysiological, and behavioral data that indicate a striking homology in the substrates that underlie the effects of mGlu2/3 receptor antagonists and the known antidepressant ketamine. The data reviewed to date also demonstrate that the preclinical side-effect/tolerability and toxicology profile of mGlu2/3 receptor antagonists are not concerning. Finally, preclinical data on a relatively new mGlu2/3 receptor antagonist, LY3020371, and its orally-bioavailable prodrug, LY3027788, are reviewed. The data on this mechanism provides optimism for successful translation of the mGlu2/3 receptor antagonist hypothesis into therapeutics for those suffering from depression.

关于氯胺酮可在患者中产生快速发作的抗抑郁作用的共识，加上最近批准的S（+）-氯胺酮（esketamine，Spravato）作为抗抑郁药，促使人们寻求其他化合物，这些化合物可概括氯胺酮的显着治疗益处。同时，发现努力还直接致力于最小化与氯胺酮相关的耐受性，副作用和安全性问题。本文回顾了关于代谢型2/3（mGlu2 / 3）受体拮抗作用的可行性的思想史，该作用机制是诱导速效抗抑郁作用的潜在机制。还提供了预测抑郁症患者中mGlu2 / 3受体拮抗剂抗抑郁功效的生物学基础。此预测是基于趋同的生化，神经化学，电生理和行为数据表明底物具有惊人的同源性，是mGlu2 / 3受体拮抗剂和已知的抗抑郁剂氯胺酮的基础。迄今为止审查的数据还表明，mGlu2 / 3受体拮抗剂的临床前副作用/耐受性和毒理学特征与研究无关。最后，综述了相对较新的mGlu2 / 3受体拮抗剂LY3020371及其口服生物利用前药LY3027788的临床前数据。关于该机制的数据为成功地将mGlu2 / 3受体拮抗剂假说转化为抑郁症患者的疗法提供了乐观。迄今为止审查的数据还表明，mGlu2 / 3受体拮抗剂的临床前副作用/耐受性和毒理学特征与研究无关。最后，综述了相对较新的mGlu2 / 3受体拮抗剂LY3020371及其口服生物利用前药LY3027788的临床前数据。关于该机制的数据为成功地将mGlu2 / 3受体拮抗剂假说转化为抑郁症患者的疗法提供了乐观。迄今为止审查的数据还表明，mGlu2 / 3受体拮抗剂的临床前副作用/耐受性和毒理学特征与研究无关。最后，综述了相对较新的mGlu2 / 3受体拮抗剂LY3020371及其口服生物利用前药LY3027788的临床前数据。关于该机制的数据为成功地将mGlu2 / 3受体拮抗剂假说转化为抑郁症患者的疗法提供了乐观。