The main objective of this study was to determine the pharmacological activity and molecular mechanism of action of DM506 (3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole fumarate), a novel ibogamine derivative, at different nicotinic acetylcholine receptor (nAChR) subtypes. The functional results showed that DM506 neither activates nor potentiates but inhibits ACh-evoked currents at each rat nAChR subtype in a non-competitive manner. The receptor selectivity for DM506 inhibition follows the sequence: α9α10 (IC₅₀ = 5.1 ± 0.3 μM) ≅ α7β2 (5.6 ± 0.2 μM) ∼ α7 (6.4 ± 0.5 μM) > α6/α3β2β3 (25 ± 1 μM) > α4β2 (62 ± 4 μM) ≅ α3β4 (70 ± 5 μM). No significance differences in DM506 potency were observed between rat and human α7 and α9α10 nAChRs. These results also indicated that the β2 subunit is not involved or is less relevant in the activity of DM506 at the α7β2 nAChR. DM506 inhibits the α7 and α9α10 nAChRs in a voltage-dependent and voltage-independent manner, respectively. Molecular docking and molecular dynamics studies showed that DM506 forms stable interactions with a putative site located in the α7 cytoplasmic domain and with two intersubunit sites in the extracellular-transmembrane junction of the α9α10 nAChR, one located in the α10(+)/α10(─) interface and another in the α10(+)/α9(─) interface. This study shows for the first time that DM506 inhibits both α9α10 and α7 nAChR subtypes by novel allosteric mechanisms likely involving modulation of the extracellular-transmembrane domain junction and cytoplasmic domain, respectively, but not by direct competitive antagonism or open channel block.

中文翻译：

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DM506（3-甲基-1,2,3,4,5,6-六氢氮杂[4,5-b]吲哚富马酸酯）是伊波胺的新型衍生物，通过不同的变构机制抑制 α7 和 α9α10 烟碱乙酰胆碱受体

本研究的主要目的是确定 DM506（3-甲基-1,2,3,4,5,6-六氢氮杂[4,5- b ]吲哚富马酸酯）的药理活性和分子作用机制，DM506 是一种新型药物。 ibogamine 衍生物，具有不同的烟碱乙酰胆碱受体 (nAChR) 亚型。功能结果表明，DM506 既不激活也不增强，而是以非竞争性方式抑制每个大鼠 nAChR 亚型的 ACh 诱发电流。DM506 抑制的受体选择性遵循以下顺序：α9α10 (IC ₅₀ = 5.1 ± 0.3 μM) ≅ α7β2 (5.6 ± 0.2 μM) ∼ α7 (6.4 ± 0.5 μM) > α6/α3β2β3 (25 ± 1 μM) > α4β2 (62 ± 4 μM) ≅ α3β4 (70 ± 5 μM)。在大鼠和人类 α7 和 α9α10 nAChR 之间未观察到 DM506 效力的显着差异。这些结果还表明，β2 亚基不参与 DM506 在 α7β2 nAChR 上的活性或不太相关。DM506 分别以电压依赖和电压无关的方式抑制 α7 和 α9α10 nAChR。分子对接和分子动力学研究表明，DM506 与位于 α7 胞质结构域的假定位点以及 α9α10 nAChR 细胞外跨膜连接处的两个亚基间位点形成稳定的相互作用，其中一个位点位于 α10(+)/α10(─ ）界面和α10（+）/α9（─）界面中的另一个。这项研究首次表明，DM506 通过新颖的变构机制抑制 α9α10 和 α7 nAChR 亚型，可能分别涉及细胞外跨膜结构域连接和细胞质结构域的调节，但不是通过直接竞争性拮抗或开放通道阻断。