Wong D T, Bymaster F P, Mayle D A, Reid L R, Krushinski J H, Robertson D W
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Neuropsychopharmacology. 1993 Jan;8(1):23-33. doi: 10.1038/npp.1993.4.
LY248686 is an inhibitor of serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) uptake in synaptosomal preparations of hypothalamus and cerebral cortex, and 5-HT uptake in human blood platelets, with inhibitor constants near nanomolar concentrations. Upon administration to rats 1 hour before sacrifice, LY248686 caused dose-dependent and parallel decreases of 5-HT and NE uptake in hypothalamus homogenates ex vivo. LY248686 is a positive enantiomer and was slightly more potent than its negative isomer, LY248685, as an inhibitor of 5-HT uptake. Both isomers were only weak inhibitors of dopamine (DA) uptake in striatal synaptosomes. The inhibitory effects on 5-HT and NE uptake after a single administration of LY248686 followed similar time courses and simultaneously persisted for as long as 6 hours. LY248686 in vivo could effectively antagonize the p-chloroamphetamine-induced decreases of 5-HT uptake and levels of 5-HT and 5-hydroxyindoleacetic acid in cerebral cortex, and block the accumulation of 14C-NE in rat hearts. In food deprived rats, LY248686 suppressed food intake synergistically with 5-hydroxytryptophan, a precursor amino acid of 5-HT. Because of its lack of affinity for receptors of 5-HT, NE, DA, acetylcholine, histamine and naloxone, and its ability to inhibit 5-HT and NE uptake simultaneously, LY248686 has a favorable pharmacological profile as a potential antidepressant drug.
LY248686是一种在下丘脑和大脑皮层突触体制剂中抑制血清素（5-羟色胺；5-HT）和去甲肾上腺素（NE）摄取以及在人血小板中抑制5-HT摄取的抑制剂，其抑制常数接近纳摩尔浓度。在处死大鼠前1小时给药，LY248686导致离体下丘脑匀浆中5-HT和NE摄取呈剂量依赖性且平行下降。LY248686是一种左旋对映体，作为5-HT摄取抑制剂，其效力略强于其右旋异构体LY248685。两种异构体均只是纹状体突触体中多巴胺（DA）摄取的弱抑制剂。单次给予LY248686后对5-HT和NE摄取的抑制作用遵循相似的时间进程，且同时持续长达6小时。LY248686在体内可有效拮抗对氯苯丙胺诱导的大脑皮层中5-HT摄取减少以及5-HT和5-羟吲哚乙酸水平降低，并阻断大鼠心脏中14C-NE的蓄积。在禁食大鼠中，LY248686与5-HT的前体氨基酸5-羟色氨酸协同抑制食物摄入。由于LY248686对5-HT、NE、DA、乙酰胆碱、组胺和纳洛酮的受体缺乏亲和力，且具有同时抑制5-HT和NE摄取的能力，因此作为一种潜在的抗抑郁药物，LY248686具有良好的药理学特性。
