DOPAMINE TRANSPORT (DAT) INHIBITORS IMPROVE PARKINSONIAN DEFICITS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在轻度至中度帕金森病中，多巴胺（DA）神经元产生DA并表达多巴胺转运体（DAT），尽管水平降低。我们假设有效的DAT抑制剂可能增加多巴胺释放水平并提供治疗益处。在mptp处理的食蟹猴中研究了8种具有低血清素转运活性的有效DAT抑制剂。与实验对象正常脑纹状体1小时内DAT占用率及DAT结合电位进行比较。在8种化合物中，6种化合物因以下原因被淘汰：3种化合物在体内无效且未能占据DAT。一种化合物占据了DAT，但其药理作用是短暂的（少于90分钟）。两种化合物在白天和晚上都增加了活性。二氟平和O-1369通过增加一般活动、改善姿势、减少身体冻结和镇静，减轻了帕金森猴子的帕金森症状。在治疗剂量下，O-1369不会增加夜间活动，而在高剂量下，二氟平会促进睡眠碎片化。与D2-D3 DA受体激动剂quinelorane相比，O-1369在增加运动活动和产生面部运动障碍方面效果较差，而quinelorane则降低了平衡，没有改善姿势，并促进了刻板印象。讨论：体外高DAT亲和力可能是必要的，但不足以预测阳性反应。改善是基于体内大脑纹状体中DAT的高占用率和受试者的晚期帕金森病，相当于DAT结合电位降低80%。多巴胺转运抑制剂对帕金森病的治疗潜力有待进一步研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In mild to moderate Parkinson's disease, dopamine (DA) neurons produce DA and express dopamine transporters (DAT), albeit at reduced levels. We postulated that potent DAT inhibitors may increase levels of released dopamine and provide therapeutic benefit. Eight potent DAT inhibitors, with low serotonin transporter activity were investigated in MPTP-treated cynomolgus monkeys. Efficacy was compared with DAT occupancy of normal brain striatum within 1 hour and DAT binding potential in experimental subjects. Of 8 compounds, 6 were eliminated from intense scrutiny for the following reasons: Three compounds were ineffective and failed to occupy the DAT in vivo. One compound occupied the DAT, but its pharmacological effects were short-lived (less than 90 minutes). Two compounds increased activity during the day and night. Difluoropine and O-1369 alleviated parkinsonian signs in parkinsonian monkeys, by increasing general activity, improving posture, reducing body freeze and sedation. O-1369 did not increase night time activity at therapeutic doses, whereas difluoropine promoted sleep fragmentation at high doses. In comparison with the D2-D3 DA receptor agonist quinelorane, O-1369 was less effective in increasing locomotor activity and produced oro-facial dyskinesias, whereas quinelorane reduced balance, did not improve posture and promoted stereotypies. Discussion: High DAT affinity in vitro may be necessary, but insufficient to predict a positive response. Improvements were predicated on high occupancy of the DAT in brain striatum in vivo and advanced parkinsonism in the subjects, equivalent to an 80% reduction of DAT binding potential. The therapeutic potential of dopamine transport inhibitors for Parkinson's disease warrants further investigation.