GSK1034702 

GSK1034702 is an orally active and allosteric agonist of M1 mAChR (pEC₅₀=8.1) that can cross the blood-brain barrier. GSK1034702 activates the Gq/11 protein-mediated signaling pathway, enhancing neuronal firing and long-term potentiation (LTP) in the CA1 region of the hippocampus. GSK1034702 can modulate hippocampal function, improve memory encoding in the nicotine withdrawal cognitive dysfunction model, and show pro-cognitive effects in rodents. GSK1034702 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].

Radioligand binding assay
GSK1034702 (1 nM-10 μM; overnight) competitively inhibits [³H]-NMS binding in CHO cells expressing human M₁ mAChR with a pKi of 6.5, and binding to M₁ receptors is not affected by DREADD mutations (Y106C/A196G)^[1].
Inositol phosphate (IP) accumulation assay
GSK1034702 (0.1 nM-10 μM; 45 min) concentration-dependently stimulates M1 receptor-mediated inositol phosphate 1 accumulation in CHO cells with an EC₅₀ of 7.1 nM and a maximal effect of 90% of ACh^[1].
ERK1/2 phosphorylation assay
GSK1034702 (0.1 nM-10 μM; 5 min) activates M₁ receptor-mediated ERK1/2 phosphorylation in CHO cells^[1].
In vitro tissue function assay
GSK1034702 inhibits the contraction induced by Methacholine (HY-A0083) (IC₅₀=8 μM), stimulates approximately 50% of the maximum Methacholine-induced contraction in rat ileum (EC₅₀=7 μM), and inhibits Methacholine-induced contraction (IC₅₀=46 μM)^[1].

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

Memory deficit reversal experiment
GSK1034702 (0.3-30 mg/kg; intraperitoneal injection; single dose) improves memory in a dose-dependent manner in the contextual fear conditioning model induced by 1.5 mg/kg Scopolamine (HY-N0296) in mice; 10 mg/kg dose reversed memory deficits^[1].
Neuron discharge enhancement experiment
GSK1034702 (1-10 mg/kg; intraperitoneal injection; acute or 7-day subchronic) increases neuronal discharge rate by 42% in the Wistar rat hippocampal model after acute administration of 10 mg/kg; subchronic administration (6 mg/kg/d) sustainedly enhances discharge and reversed Scopolamine (HY-N0296)-induced passive avoidance memory deficits^[1].

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

333.40

C₁₈H₂₄FN₃O₂

932373-87-0

Solid

White to off-white

CC1=CC2=C(NC(N2C3CCN(C4CCOCC4)CC3)=O)C(F)=C1

Room temperature in continental US; may vary elsewhere.

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

• [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]