Benztropine Analogs, Cocaine Abuse Pharmacotherapies

描述（由申请人提供）：有效的药物治疗剂的识别仍然是可卡因滥用治疗的主要挑战。可卡因的高滥用潜力被认为部分是由于其起效快和作用持续时间短，这与其药代动力学（PK）和药效学（PD）特性直接相关。这表明不同于可卡因的PK和PD特征将是替代治疗剂的期望特征。基于“替代疗法”开发的药物与多巴胺转运蛋白（DAT）结合，抑制多巴胺（DA）再摄取，并延长DA水平，其程度低于可卡因。因此，其替代治疗剂的BBB转运、分布和处置应反映所谓的精神活性药物作用的速率假设。这意味着它们应该显示出缓慢的体循环输入和缓慢的身体清除。BZT类似物，DA摄取抑制剂，以更高的亲和力与DAT结合，但不是有效的运动刺激剂。在初步研究中，与可卡因相比，选择的BZT类似物显示出穿过BBB的高渗透性、缓慢的处置和长持续时间的DA升高。从这些研究中，似乎BZT类似物的结构和理化性质是其BBB运输，处置和DA升高的决定因素。因此，我们的中心假设是BZT类似物的BBB转运、PK和PD依赖于它们的结构修饰（例如，取代、对映体状态、亲脂性等）和所得的理化性质。为了检验这一假设，将追求以下具体目标：SA 1。通过使用BBMEC检查结构和理化差异来确定BZT类似物的BBB渗透性。SA2表征大鼠IV和经口给药后BZT类似物的脑摄取和PK。SA 3：使用微透析表征大鼠IV和口服给药后BZT类似物和可卡因的PD（例如，多巴胺释放）。SA 4.表征IV和口服给药后选定BZT类似物和可卡因的PK和PD相互作用。这些研究对于替代疗法的进一步评价至关重要，并将阐明对可卡因滥用有效药物治疗所需的BBB转运、PK和相关PD特征至关重要的结构相关特征。

DESCRIPTION (provided by applicant): Identification of effective pharmacotherapeutic agents continues to be a major challenge in the treatment of cocaine abuse. The high abuse potential of cocaine is believed to be in part due to its rapid onset and short duration of action which directly correlates with its pharmacokinetic (PK) and pharmacodynamic (PD) properties. This suggests that a PK and PD profile different from cocaine would be desired characteristic for a substitute therapeutic agent. Agents developed based on the "substitute therapy approach" bind to the dopamine transporter (DAT), inhibit dopamine (DA) reuptake, and prolong DA levels to a lesser extent than cocaine. As such, their BBB transport, distribution and disposition of a substitute therapeutic agent should reflect the so-called rate hypothesis of psychoactive drug effect. This means that they should display a slow input into the systemic circulation and slow clearance from the body. The BZT analogs, DA uptake inhibitors, bind with higher affinity to the DAT, but are not efficacious locomotor stimulants. In preliminary studies, select BZT analogs display high permeability across the BBB, a slow disposition and a long duration of DA elevation in comparison to cocaine. From these studies, it appears that the BZT analog structure and physiochemical properties are determining factors in their BBB transport, disposition and DA elevation. As such, our central hypothesis is that the BBB transport, PK and PD of the BZT analogs, is dependent on their structural modifications (e.g., substitution, enantiomer status, lipophilcity, etc) and resultant physiochemical properties. To examine this hypothesis, the following specific aims will be pursued: SA1. Determine the BBB permeability of BZT analogs by examining structural and physiochemical differences using BBMECs. SA2 Characterize the brain uptake and PK of BZT analogs after IV and oral dosing to rats. SA 3: Characterize the PD (e.g, dopamine release) of the BZT analogs and cocaine after IV and oral dosing to rats using microdialysis. SA 4. Characterize the PK and PD interaction of select BZT analogs and cocaine after IV and oral dosing. These studies are essential to the further evaluation of substitute therapeutics and will elucidate the structural related features that are important in the BBB transport, PK and associated PD characteristics required for effective pharmacotherapy for cocaine abuse.