Harvey B D, Siok C J, Kiss T, Volfson D, Grimwood S, Shaffer C L, Hajós M
Neuroscience Research Unit, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA.
Research Statistics, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA.
Neuropharmacology. 2013 Dec;75:19-30. doi: 10.1016/j.neuropharm.2013.06.020. Epub 2013 Jul 4.
The Group I metabotropic glutamate receptor subtype 5 (mGluR5) is widely distributed in the brain with dense expression in the cerebral cortex, hippocampus, and basal ganglia. These receptors have been implicated in psychiatric and neurological disorders such as schizophrenia, Fragile X syndrome, addiction, anxiety/depression, Parkinson's disease and neuropathic pain. The present study evaluated the effects of the mGluR5 negative allosteric modulators (NAMs) 4-difluoromethoxy-3-(pyridine-2-ylethynyl)phenyl)5H-pyrrolo[3,4-b]pyridine-6(7H)-yl methanone (GRN-529) and methyl (3aR,4S,7aR)-4-hydroxy-4-[(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate (AFQ056) on polysomnographic (PSG) and quantitative electroencephalographic (qEEG) measures in freely moving rats. Furthermore, the anxiolytic profile of GRN-529 was characterized in anesthetized rats by measuring stimulation-induced hippocampal theta oscillation. The present findings demonstrate that inhibition of mGluR5 via its allosteric site profoundly modulates high-level neuronal network activities as indicated by changes in sleep-wake activity and power distribution of qEEG. Both GRN-529 and AFQ056 reduced the total time spent in rapid-eye movement with AFQ056 producing a significant increase in wakefulness at the highest dose tested. Additionally, qEEG revealed significant compound-induced increases in delta power concomitant with more subtle decreases in theta and alpha band power. Receptor occupancy (RO) studies revealed that GRN-529 and AFQ056 at all doses resulted in over 45% mGluR5 occupancy. Furthermore, GRN-529 dose-dependently decreased elicited hippocampal theta frequency, consistent with previous findings using clinically active anxiolytic compounds. The described changes in neurophysiological signals identified in freely moving rats may be considered suitable translational biomarkers for the clinical evaluation of mGluR5 NAMs.
I 型代谢型谷氨酸受体 5 亚型（mGluR5）广泛分布于大脑中，在大脑皮层、海马体和基底神经节中表达密集。这些受体与精神疾病和神经疾病有关，如精神分裂症、脆性 X 综合征、成瘾、焦虑/抑郁、帕金森病和神经性疼痛。本研究评估了 mGluR5 负变构调节剂（NAMs）4-二氟甲氧基-3-（吡啶-2-基乙炔基）苯基）5H-吡咯并[3,4-b]吡啶-6（7H）-基甲酮（GRN-529）和甲基（3aR,4S,7aR）-4-羟基-4-[(3-甲基苯基)乙炔基]八氢-1H-吲哚-1-羧酸酯（AFQ056）对自由活动大鼠多导睡眠图（PSG）和定量脑电图（qEEG）指标的影响。此外，通过测量刺激诱导的海马体θ振荡，在麻醉大鼠中对 GRN-529 的抗焦虑特征进行了表征。本研究结果表明，通过其变构位点抑制 mGluR5 可深刻调节高水平的神经网络活动，如睡眠-觉醒活动和 qEEG 的功率分布变化所示。GRN-529 和 AFQ056 均减少了快速眼动睡眠的总时长，AFQ056 在测试的最高剂量下使清醒时间显著增加。此外，qEEG 显示化合物诱导的δ功率显著增加，同时θ和α频段功率有更细微的降低。受体占有率（RO）研究表明，所有剂量的 GRN-529 和 AFQ056 均导致 mGluR5 占有率超过 45%。此外，GRN-529 剂量依赖性地降低了诱发的海马体θ频率，这与先前使用临床活性抗焦虑化合物的研究结果一致。在自由活动大鼠中确定的神经生理信号的上述变化可被视为 mGluR5 NAMs 临床评估的合适转化生物标志物。
