The anxiolytic and sedative-like effects of 3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (DM506), a non-hallucinogenic compound derived from ibogamine, were studied in mice. The behavioral effects were examined using Elevated O-maze and novelty suppressed feeding (NSFT) tests, open field test, and loss of righting reflex (LORR) test. The results showed that 15 mg/kg DM506 induced acute and long-lasting anxiolytic-like activity in naive and stressed/anxious mice, respectively. Repeated administration of 5 mg/kg DM506 did not cause cumulative anxiolytic activity or any side effects. Higher doses of DM506 (40 mg/kg) induced sedative-like activity, which was inhibited by a selective 5-HT_2A receptor antagonist, volinanserin. Electroencephalography results showed that 15 mg/kg DM506 fumarate increased the transition from a highly alert state (fast γ wavelength) to a more synchronized deep-sleeping activity (δ wavelength), which is reflected in the sedative/anxiolytic activity in mice but without the head-twitch response observed in hallucinogens. The functional, radioligand binding, and molecular docking results showed that DM506 binds to the agonist sites of human 5-HT_2A (Ki = 24 nM) and 5-HT_2B (Ki = 16 nM) receptors and activates them with a potency (EC₅₀) of 9 nM and 3 nM, respectively. DM506 was relatively less potent and behaved as a partial agonist (efficacy <80%) for both receptor subtypes compared to the full agonist DOI (2,5-dimethoxy-4-iodoamphetamine). Our study showed for the first time that the non-hallucinogenic compound DM506 induces anxiolytic- and sedative-like activities in naïve and stressed/anxious mice in a dose-, time-, and volinanserin-sensitive manner, likely through mechanisms involving 5-HT_2A receptor activation.

在小鼠身上研究了3-甲基-1,2,3,4,5,6-六氢氮杂[4,5-b]吲哚 (DM506) 的抗焦虑和镇静作用，DM506 是一种源自伊波格明的非致幻化合物。。使用高架 O 迷宫和新奇抑制进食 (NSFT) 测试、旷场测试和翻正反射丧失(LORR) 测试来检查行为效果。结果表明，15 mg/kg DM506 分别在幼稚小鼠和应激/焦虑小鼠中诱导急性和持久的抗焦虑样活性。重复给予 5 mg/kg DM506 不会引起累积抗焦虑活性或任何副作用。较高剂量的 DM506 (40 mg/kg) 会诱导镇静样活性，该活性可被选择性 5-HT _2A受体拮抗剂沃林色林 (volinanserin)抑制。脑电图结果显示，15 mg/kg DM506 富马酸盐增加了从高度警觉状态（快 γ 波长）到更同步的深度睡眠活动（δ 波长）的转变，这反映在小鼠的镇静/抗焦虑活性中，但没有在致幻剂中观察到的头部抽搐反应。功能、放射性配体结合和分子对接结果表明，DM506 与人 5-HT _2A (Ki = 24 nM) 和 5-HT _2B (Ki = 16 nM) 受体的激动剂位点结合，并以效力 (EC) 激活它们。₅₀ )分别为9nM和3nM。与完全激动剂 DOI（2,5-二甲氧基-4-碘苯丙胺）相比， DM506 的效力相对较低，并且对两种受体亚型均表现为部分激动剂（功效 <80%）。我们的研究首次表明，非致幻性化合物 DM506 可能通过涉及 5-HT 的机制，以剂量、时间和伏林色林敏感的方式在幼稚小鼠和应激/焦虑小鼠中诱导抗焦虑和镇静样活性_2A受体激活。