DS2 is a novel and selective positive allosteric modulator of δ-subunit-containing GABAA receptors. DS2 enhances the function of extrasynaptic δ-GABAA receptors by increasing the maximal response to GABA, while acting via an unknown site to provide receptor subunit selectivity[1-2]. DS2 is used to study the function of extrasynaptic δ-GABAA receptors and their role in stroke recovery[3-4].
In vitro, HEK293 cells stably expressing the human δ subunit were co-incubated with DS2 (1–5μM) and GABA (EC₂₅–₃₅) to measure the current response. DS2 selectively potentiated the current response or fluorescence signal at δ-GABAA receptors (α₄β₁δ and α₄β₃δ)[5]. Mouse thalamic ventrobasal (VB) neurons and cerebellar granule cells (CGCs) were pretreated with DS2 (3–10µM) for 30 seconds before recording in the presence of ambient GABA. DS2 significantly enhanced the tonic inhibitory current mediated by δ-subunit-containing δ-GABAA receptors[6].
In vivo, in the AppNL-F KI AD mouse model aged 12-16 months, DS2 (1-4mg/kg) was administered via intraperitoneal injection once daily for 5 consecutive days. DS2 significantly reduced anxiety-like behaviors and normalized the expression of δ-GABAA receptors[7]. In male C57BL/6J mice after stroke, DS2 (0.1-4mg/kg) was administered via intraperitoneal injection twice, at 1 hour and 24 hours post-stroke. DS2 significantly reduced infarct volume, improved motor function in the grid-walking and cylinder tasks, and lowered the levels of circulating pro-inflammatory cytokines (TNF-α, IL-6, IL-17)[8].
References:
[1] Lee HJ, Absalom NL, Hanrahan JR, et al. A pharmacological characterization of GABA, THIP and DS2 at binary α4β3 and β3δ receptors: GABA activates β3δ receptors via the β3(+)δ(-) interface. Brain Res. 2016 Aug 1;1644:222-30.
[2] Jensen ML, Wafford KA, Brown AR, et al. A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA(A) receptors. Br J Pharmacol. 2013 Mar;168(5):1118-32.
[3] Jensen NN, Wilhelmsen KS, Jensen MH, et al. Exploring the DS2 Scaffold for GABAA Receptor Modulation: Progress toward the Development of a GABAA δ-Subunit Preferring Negative Allosteric Modulator. J Med Chem. 2026 Feb 26;69(4):3811-3832.
[4] Rostrup F, Falk-Petersen CB, Harpso E K, et al. Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors. J Med Chem. 2021 Apr 22;64(8):4730-4743.
[5] Falk-Petersen CB, Søgaard R, Madsen KL, et al. Development of a Robust Mammalian Cell-based Assay for Studying Recombinant α4 β1/3 δ GABAA Receptor Subtypes. Basic Clin Pharmacol Toxicol. 2017 Aug;121(2):119-129.
[6] Wafford KA, van Niel MB, Ma QP, et al. Novel compounds selectively enhance delta subunit containing GABA A receptors and increase tonic currents in thalamus. Neuropharmacology. 2009 Jan;56(1):182-9.
[7] Zhang W, Liu T, Li J, et al. Decreased extrasynaptic δ-GABAA receptors in PNN-associated parvalbumin interneurons correlates with anxiety in APP and tau mouse models of Alzheimer's disease. Br J Pharmacol. 2024 Oct;181(20):3944-3975.
[8] Neumann S, Boothman-Burrell L, Gowing EK, et al. The Delta-Subunit Selective GABA A Receptor Modulator, DS2, Improves Stroke Recovery via an Anti-inflammatory Mechanism. Front Neurosci. 2019 Oct 29;13:1133.
DS2是一种新型的、具有选择性的δ-GABAA受体正变构调节剂。DS2通过增强GABA的最大反应来增强突触外δ-GABAA受体的功能，同时通过未知位点发挥作用以提供受体亚型选择性[1-2]。DS2可用于研究突触外δ-GABAA受体功能和中风恢复的相关研究[3-4]。
在体外，DS2（1–5μM）和GABA（EC₂₅–₃₅）同时孵育稳定表达人δ亚基的HEK293细胞时，检测细胞的电流反应。DS2能选择性地增强δ-GABAA受体（α₄β₁δ和α₄β₃δ）的电流反应或荧光信号[5]。DS2（3–10µM）预处理小鼠丘脑腹基底核（VB）神经元及小脑颗粒细胞（CGCs）30秒，随后在环境GABA存在下进行记录。DS2显著增强由δ-GABAA受体介导的紧张性（tonic）抑制电流[6]。
在体内，DS2（1-4mg/kg）每天一次腹腔注射，连续5天，用于处理12-16月龄的AppNL-F KI AD小鼠模型。DS2显著减少了小鼠的焦虑行为，并正常化了δ-GABAA受体的表达[7]。DS2（0.1-4mg/kg）于中风后1小时及24小时腹腔注射两次，用于中风C57BL/6J雄性小鼠。DS2显著减小了梗死体积，改善了网格行走和圆筒任务中的运动功能，并降低了循环促炎细胞因子（TNF-α，IL-6，IL-17）的水平[8]。