Preclinical characterization of WAY-211612: a dual 5-HT uptake inhibitor and 5-HT1A receptor antagonist and potential novel antidepressant

Background and purpose

As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT_1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT_1A receptor antagonist activities, was evaluated in preclinical models.

Experimental approach

Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models.

Key results

WAY-211612 inhibited 5-HT reuptake (K_i = 1.5 nmol·L⁻¹; K_B = 17.7 nmol·L⁻¹) and exhibited full 5-HT_1A receptor antagonist activity (K_i = 1.2 nmol·L⁻¹; K_B = 6.3 nmol·L⁻¹; I_max 100% in adenyl cyclase assays; K_B = 19.8 nmol·L⁻¹; I_max 100% in GTPγS). WAY-211612 (3 and 30 mg·kg⁻¹, po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT_1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3–30 mg·kg⁻¹, po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg⁻¹, s.c.) and a 5-HT_1A antagonist (WAY-100635; 0.3 mg·kg⁻¹, s.c). WAY-211612 (3.3–30 mg·kg⁻¹, s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3–30 mg·kg⁻¹, i.p. and 10–56 mg·kg⁻¹, po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg·kg⁻¹, i.p.) in the rat scheduled-induced polydipsia model.

Conclusions and implications

These findings suggest that WAY-211612 may represent a novel antidepressant.     

膳食补充剂黑醋与红曲单用及联用对中老年人血脂的影响

目的:观察并比较黑醋与红曲单用及联用对中国中老年人降低血脂的效能。方法:试验于2003-10/11在大连医科大学中日合作医药科学研究所进行。选择30名年龄为45￣65岁的中老年人。30名受试者被随机分为3组,每组10人,分别服用黑醋丸6粒,红曲丸6粒或黑醋 红曲丸6粒,1次/d,连续4周;3种膳食补充剂黑醋丸、红曲丸及黑醋 红曲丸由含有不同剂量的黑醋固形物、红曲粉末K-F、柠檬酸钠、大豆油、蜂蜡、脂肪酸甘油脂组成(由日本国第一药品工业株式会社提供)。各组服用剂量分别为每天黑醋固形物360mg,红曲粉72mg及黑醋固形物360mg 红曲粉72mg。服用2和(或)4周后,检测血脂和血糖,同时用血清样品检测肝功与肾功能。实验结果用SPSS统计软件进行方差分析。结果:30名中老年人全部进入结果分析。①受试者连续3d每日营养素摄入量:3组之间热量、胆固醇、膳食纤维、宏量或微量营养素摄入量差距均无显著性。②血清脂质浓度和计算的脂质比:2,4周血清三酰甘油含量,黑醋 红曲组低于基础值(分别下降(24.6±4.9)%,(27.6±3.4)%,P<0.05);红曲组与基础值比较,差异无显著性[分别下降(6.5±3.4)%,(11.6±4.5)%];黑醋组与基础值比较,差异无显著性[分别下降(10.2±7.3)%,(12.4±8.2)%]。2,4周血清胆固醇、低密度脂蛋白胆固醇含量,黑醋 红曲丸、红曲丸和黑醋丸组均比基础值降低,差异无统计学意义。3种膳食补充剂对血清高密度脂蛋白胆固醇及计算的脂质比值无明显改变。血糖含量无变化。未发现对受试对象产生明显不良反应。结论:服用黑醋 红曲丸能明显降低受试者血清三酰甘油含量。黑醋与红曲合用对高脂血症者可能有健康效益。     

子宫内膜异位症患者血清细胞因子水平的测定

子宫内膜异位症患者血清细胞因子水平的测定程凯灵令狐华子宫内膜异位症（ＥＭＳ）是妇科常见病。国内外学者的研究表明，免疫学的变化在该病的病理生理学中有重要意义。本研究通过酶联免疫吸附试验（ＥＬＩＳＡ），对ＥＭＳ患者血清细胞因子［白细胞介素（ＩＬ）－６、Ｉ...