Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
Neuropharmacology. 2023 Nov 1;238:109644. doi: 10.1016/j.neuropharm.2023.109644. Epub 2023 Jul 6.
Type-A and -B GABA receptors (GABARs/GABARs) control brain function and behaviour by fine tuning neurotransmission. Over-time these receptors have become important therapeutic targets for treating neurodevelopmental and neuropsychiatric disorders. Several positive allosteric modulators (PAMs) of GABARs have reached the clinic and selective targeting of receptor subtypes is crucial. For GABARs, CGP7930 is a widely used PAM for in vivo studies, but its full pharmacological profile has not yet been established. Here, we reveal that CGP7930 has multiple effects not only on GABARs but also GABARs, which for the latter involves potentiation of GABA currents, direct receptor activation, and also inhibition. Furthermore, at higher concentrations, CGP7930 also blocks G protein-coupled inwardly-rectifying K (GIRK) channels diminishing GABAR signalling in HEK 293 cells. In male and female rat hippocampal neuron cultures, CGP7930 allosteric effects on GABARs caused prolonged rise and decay times and reduced the frequency of inhibitory postsynaptic currents and potentiated GABAR-mediated tonic inhibition. Additional comparison between predominant synaptic- and extrasynaptic-isoforms of GABAR indicated no evident subtype selectivity for CGP7930. In conclusion, our study of CGP7930 modulation of GABARs, GABARs and GIRK channels, indicates this compound is unsuitable for use as a specific GABAR PAM.
A 型和 B 型 GABA 受体（GABARs/GABARs）通过微调神经递质传递来控制大脑功能和行为。随着时间的推移，这些受体已成为治疗神经发育和神经精神疾病的重要治疗靶点。几种 GABA 受体的正变构调节剂（PAMs）已进入临床，受体亚型的选择性靶向至关重要。对于 GABA 受体，CGP7930 是一种广泛用于体内研究的 PAM，但它的全药理学特性尚未确定。在这里，我们揭示 CGP7930 不仅对 GABA 受体而且对 GABA 受体具有多种作用，后者涉及 GABA 电流的增强、受体的直接激活以及抑制。此外，在较高浓度下，CGP7930 还会阻断 G 蛋白偶联内向整流钾（GIRK）通道，从而减少 HEK 293 细胞中 GABA 受体信号。在雄性和雌性大鼠海马神经元培养物中，CGP7930 对 GABA 受体的变构作用导致 GABA 受体的上升和下降时间延长，抑制性突触后电流频率降低，并增强 GABA 介导的紧张性抑制。GABAR 主要突触型和 extrasynaptic-isoforms 之间的进一步比较表明，CGP7930 对其没有明显的亚型选择性。总之，我们对 CGP7930 对 GABA 受体、GABAR 受体和 GIRK 通道的调节研究表明，该化合物不适合用作特定的 GABA 受体 PAM。
