GSK1034702 hydrochloride 

GSK1034702 hydrochloride is an orally active and allosteric agonist of M1 mAChR (pEC₅₀=8.1) that can cross the blood-brain barrier. GSK1034702 hydrochloride activates the Gq/11 protein-mediated signaling pathway, enhancing neuronal firing and long-term potentiation (LTP) in the CA1 region of the hippocampus. GSK1034702 hydrochloride can modulate hippocampal function, improve memory encoding in the nicotine withdrawal cognitive dysfunction model, and show pro-cognitive effects in rodents. GSK1034702 hydrochloride can be used for the study of the mechanisms of cognitive impairment diseases such as Alzheimer's disease, and has certain peripheral M receptor activation-related side effects (such as gastrointestinal reactions)^[1][2].

放射性配体结合实验
GSK1034702 hydrochloride (1 nM-10 μM；过夜) 竞争性抑制表达人 M₁ mAChR 的 CHO 细胞中 [³H]-NMS 结合，pKi 为 6.5，且对 M₁ 受体的结合不受 DREADD 突变 (Y106C/A196G) 影响^[1]。
肌醇磷酸 (IP) 积累实验
GSK1034702 hydrochloride (0.1 nM-10 μM；45 min) 浓度依赖性刺激 CHO 细胞中 M1 受体介导的 Inositol Phosphate 1 积累，EC₅₀ 为 7.1 nM，最大效应为 ACh 的 90%^[1]。
ERK1/2磷酸化实验
GSK1034702 hydrochloride (0.1 nM-10 μM；5 min) 激活 CHO 细胞中 M₁ 受体介导的 ERK1/2 磷酸化^[1]。
离体组织功能实验
GSK1034702 hydrochloride 可抑制 Methacholine (HY-A0083) 的诱导收缩反应 (IC₅₀=8 μM)，在大鼠回肠中，刺激了约 50% 的最大 Methacholine 引起的收缩反应 (EC₅₀=7 μM)，并抑制了 Methacholine 诱导的收缩 (IC₅₀=46 μM)^[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

记忆缺陷逆转实验
GSK1034702 (0.3-30 mg/kg；腹腔注射；单次) hydrochloride 在 1.5 mg/kg Scopolamine (HY-N0296) 诱导的小鼠情境恐惧条件反射模型中，呈剂量依赖性改善记忆；10 mg/kg 剂量下课逆转记忆缺陷^[1]。
神经元放电增强实验
GSK1034702 (1-10 mg/kg；腹腔注射；急性或 7 天亚慢性) hydrochloride 在 Wistar 大鼠海马模型中，急性给药 10 mg/kg 使神经元放电率增加 42%；亚慢性给药 (6 mg/kg/d) 可持续增强放电并逆转 Scopolamine (HY-N0296) 诱导的被动回避记忆缺陷^[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

369.86

C₁₈H₂₅ClFN₃O₂

932373-86-9

Room temperature in continental US; may vary elsewhere.

Please store the product under the recommended conditions in the Certificate of Analysis.

• [1]. Bradley SJ, et al. Bitopic Binding Mode of an M1 Muscarinic Acetylcholine Receptor Agonist Associated with Adverse Clinical Trial Outcomes. Mol Pharmacol. 2018 Jun;93(6):645-656.  [Content Brief]

  [2]. Nathan PJ, et al. The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction. Int J Neuropsychopharmacol. 2013 May;16(4):721-31.  [Content Brief]