Dressman Bruce A, Tromiczak Eric G, Chappell Mark D, Tripp Allie E, Quimby Steven J, Vetman Tatiana, Fivush Adam M, Matt James, Jaramillo Carlos, Li Renhua, Khilevich Albert, Blanco Maria-Jesus, Smith Stephon C, Carpintero Mercedes, de Diego José Eugenio, Barberis Mario, García-Cerrada Susana, Soriano José F, Schkeryantz Jeffrey M, Witkin Jeffrey M, Wafford Keith A, Seidel Wesley, Britton Thomas, Overshiner Carl D, Li Xia, Wang Xu-Shan, Heinz Beverly A, Catlow John T, Swanson Steven, Bedwell David, Ornstein Paul L, Mitch Charles H
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Bioorg Med Chem Lett. 2016 Dec 1;26(23):5663-5668. doi: 10.1016/j.bmcl.2016.10.067. Epub 2016 Oct 25.
Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu IC 46±14.2nM, hmGlu IC=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu receptors both in vitro and in vivo.
代谢型谷氨酸2和3受体的负性调节剂在动物模型中表现出抗抑郁样活性，有望成为治疗重度抑郁症的新型治疗药物。在此，我们描述了制备和优化一系列构象受限的3,4-二取代双环[3.1.0]己烷谷氨酸类似物作为变构（谷氨酸位点）mGlu受体拮抗剂的工作。这项工作导致发现了一种高效且有效的工具化合物18（hmGlu IC₅₀ = 46 ± 14.2 nM，hmGlu IC = 46.1 ± 36.2 nM）。化合物18在小鼠强迫游泳试验中显示出活性，腹腔注射的最小有效剂量（MED）为1 mg/kg。而在大鼠脑电图研究中，它在腹腔注射3和10 mg/kg时表现出促觉醒作用，对运动活动没有任何显著影响。因此，化合物18代表了一种新型工具分子，可用于研究在体外和体内阻断mGlu受体的影响。
