Neuroscience Research Unit, Pfizer Global Research, 700 Main Street, Cambridge, MA 02139, USA.
Neuropharmacology. 2013 Mar;66:202-14. doi: 10.1016/j.neuropharm.2012.04.007. Epub 2012 Apr 21.
Evidence suggests that 30-50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction. Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1-30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
有证据表明，30-50%患有重度抑郁症（MDD）的患者被归类为治疗抵抗性抑郁症（TRD），因为他们对标准抗抑郁药没有足够的反应。这部分患者的一个主要特征是焦虑和疼痛等合并症状的发生率增加。鉴于当前的护理标准主要集中在单胺能作用机制（MOAs）上，针对 TRD 的药物发现的创新方法是针对谷氨酸功能亢进。在这里，我们描述了新型代谢型谷氨酸受体 5（mGluR5）的负变构调节剂（NAM）GRN-529 的体外和体内特征。在基于细胞的药理学测定中，GRN-529 是一种高亲和力（Ki 5.4 nM）、强效（IC50 3.1 nM）和选择性（> 1000 倍选择性比 mGluR1）的 mGluR5 NAM。GRN-529（0.1-30 mg/kg po）的急性给药在一组具有治疗相关性的动物模型中具有剂量依赖性疗效，包括抑郁（悬尾和强迫游泳试验中不动时间减少）和 TRD 中过度代表的两种合并症状，即焦虑（应激诱导的体温升高减弱，以及在四板试验中增加受罚穿越）和疼痛（坐骨神经结扎或炎症引起的痛觉过敏逆转）。还使用临床前模型评估了 GRN-529 的潜在副作用：GRN-529 对大鼠性行为或运动协调（旋转棒）没有影响，但它损害了小鼠的认知（社交气味识别）。将 GRN-529 的疗效和副作用与标准护理剂（抗抑郁药、抗焦虑药或镇痛药）和工具 mGluR5 NAM、MTEP 进行了比较。为了评估靶标占有率和疗效之间的关系，在进行疗效测试的同时平行测量了体外受体占有率。这表明在行为终点之间，靶标结合、暴露和疗效之间存在很强的相关性，这支持了 PET 成像在患者剂量选择中的潜在转化价值。GRN-529 的这种广谱疗效谱支持我们的假设，即 mGluR5 的负变构调节可能代表治疗 TRD 的一种创新治疗方法。本文是特刊“代谢型谷氨酸受体”的一部分。
