We report here the synthesis and characterization of a dual 5-HT₇ 5-HT₂ receptor antagonist 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT₇ and 5-HT_2A receptor ligand having a pK_i = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5-HT_2A and as an inverse agonist in an in vitro functional assay for 5-HT₇. In a validated in vivo model for central 5-HT₇ activity in rats, blockade of 5-Carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED₅₀ = 0.05 mg/kg, p.o., 1 h) and maximal efficacy was observed at 0.3 mg/kg p.o. with a corresponding plasma concentration of ∼ 27 ng/ml. In a validated in vivo model for central 5-HT_2A activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED₅₀ = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT_2A receptor binding sites in the frontal cortex of the rat brain with an ED₅₀ in good agreement with the ED₅₀ value for central functional effect mediated by 5-HT_2A receptor (ED₅₀ = 0.8 mg/kg, p.o., 1h).

我们在这里报告了双重5-HT ₇ 5-HT ₂受体拮抗剂3-（4-氟-苯基）-2-异丙基-2,4,5,6,7,8-hexahydro-1的合成和表征2,6-三氮杂氮烯（4j）。4j是在两个受体上均具有pK _i＝ 8.1的高亲和力5-HT ₇和5-HT _2A受体配体。它在5-HT _2A的体外功能测定中起拮抗剂作用，在5-HT _7的体外功能测定中起反向激动剂作用。在经过验证的中心5-HT ₇体内模型中大鼠体内的活性，阻断5-羧酰胺基色胺（5-CT）引起的体温过低，4j显示了低剂量（ED ₅₀ = 0.05 mg / kg，po，1 h）的功效，观察到最大剂量为0.3 mg / kg po的功效。相应的血浆浓度约为27 ng / ml。在经过验证的体内中心5-HT _2A活性模型中，2,5-二甲氧基-4-碘安非他明（DOI）引起的小鼠头部抽搐的阻滞，4j显示了低剂量的ED ₅₀ = 0.3 mg / kg的功效PO体外受体结合研究表明，4J占据5-HT _2A受体结合的大鼠脑额叶皮层部位与ED ₅₀与ED一致5-HT _2A受体介导的中枢功能作用的₅₀值（ED ₅₀ = 0.8 mg / kg，口服，1h）。