Cecere Giuseppe, Ballard Theresa M, Knoflach Frederic, Honer Michael, Hipp Joerg F, Garces Pilar, Mueggler Thomas, Künnecke Basil, Bruns Andreas, Prinssen Eric P, Schoenenberger Philipp, Janz Philipp, Redondo Roger, Biemans Barbara, Knust Henner, Olivares-Morales Andrés, Brigo Alessandro, Schulz Jan Michael, Bertrand Daniel, Saxe Michael, O'Connor Eoin C, Hernandez Maria-Clemencia
Medicinal Chemistry, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
Neuroscience and Rare Diseases, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
Front Pharmacol. 2025 Jul 21;16:1626078. doi: 10.3389/fphar.2025.1626078. eCollection 2025.
Alterations in the GABAergic system contribute to the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD) and Angelman syndrome (AS), particularly in cases involving large deletions in the 15q11-13 region. Positive modulation of GABA-α5 receptors may provide a novel therapeutic approach without the typical side effects associated with non-selective GABA positive allosteric modulators such as diazepam.
Alogabat was assessed for binding and functional activity at GABA-α5β3γ2 receptors and in electrophysiological studies using hippocampal slices. studies in rodents included receptor occupancy (RO) using a selective GABA-α5 tracer (autoradiography), pharmacological MRI, and electroencephalography (EEG). Alogabat was evaluated for its effects on the repetitive behavior phenotype in BTBR and contactin-associated protein-like 2 (Cntnap2) knockout mice, seizure models, cognitive performance in rats, and rotarod performance following combination treatment with diazepam.
Alogabat is a potent positive allosteric modulator of GABA-α5 receptors, with binding and functional selectivity. Receptor occupancy studies provided direct proof of dose-dependent target engagement. Functional circuit modulation was demonstrated by dose-dependent regional perfusion changes in pharmacological MRI and changes in EEG theta- and beta-band power in rats. At >50% GABA-α5 receptor occupancy, alogabat normalized elevated self-grooming behavior in both Cntnap2 and BTBR mice and exhibited antiepileptic activity in rats. Alogabat did not impair cognition in wildtype rats at GABA-α5 receptor occupancy up to 75%, although impairment occurred at higher doses, probably due to increased activity at other receptor subtypes and/or saturation of α5 receptors. Alogabat did not worsen diazepam-induced impairment on the rotarod test.
Alogabat showed beneficial effects in mouse models relevant to neurodevelopmental disorders and anti-seizure activity at doses that did not produce cognitive, sedative, or motoric side effects.
γ-氨基丁酸（GABA）能系统的改变促成了神经发育障碍的病理生理学过程，包括自闭症谱系障碍（ASD）和天使综合征（AS），特别是在涉及15q11 - 13区域大片段缺失的病例中。对GABA-α5受体的正向调节可能提供一种新的治疗方法，而没有与非选择性GABA正向变构调节剂（如地西泮）相关的典型副作用。
使用海马切片在GABA-α5β3γ2受体上评估阿洛加巴特的结合和功能活性，并进行电生理研究。在啮齿动物中的研究包括使用选择性GABA-α5示踪剂（放射自显影）进行受体占有率（RO）研究、药理磁共振成像（MRI）和脑电图（EEG）。评估了阿洛加巴特对BTBR和接触蛋白相关蛋白样2（Cntnap2）基因敲除小鼠的重复行为表型、癫痫模型、大鼠认知能力以及与地西泮联合治疗后的转棒试验表现的影响。
阿洛加巴特是GABA-α5受体的强效正向变构调节剂，具有结合和功能选择性。受体占有率研究提供了剂量依赖性靶点结合的直接证据。药理MRI中剂量依赖性区域灌注变化以及大鼠EEG中θ波和β波功率变化证明了功能回路调节。在GABA-α5受体占有率>50%时，阿洛加巴特使Cntnap2和BTBR小鼠的过度自我梳理行为恢复正常，并在大鼠中表现出抗癫痫活性。在GABA-α5受体占有率高达75%时，阿洛加巴特不会损害野生型大鼠的认知能力，尽管在更高剂量时会出现损害，这可能是由于其他受体亚型的活性增加和/或α5受体饱和所致。阿洛加巴特不会加重地西泮诱导的转棒试验损伤。
阿洛加巴特在与神经发育障碍相关的小鼠模型中显示出有益作用，并且在不产生认知、镇静或运动副作用的剂量下具有抗癫痫活性。
