Benztopine Analogs, Cocaine Abuse Pharmacotherapies

描述(由申请人提供)：确定有效的药物治疗剂仍然是治疗可卡因滥用的主要挑战。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，与可卡因不同的PK和PD特征将是替代治疗药物的理想特征。基于“替代疗法”开发的药物与多巴胺转运体(DAT)结合，抑制多巴胺(DA)的再摄取，并在较小程度上延长DA的水平。因此，它们的血脑屏障转运、分布和替代治疗药物的处置应反映所谓的精神活性药物效应的比率假说。这意味着它们应该表现出对体循环的缓慢输入和对身体的缓慢清除。BZT类似物，DA摄取抑制剂，与DAT结合有更高的亲和力，但不是有效的运动刺激剂。在初步研究中，与可卡因相比，部分BZT类似物显示出通过血脑屏障的高渗透性、缓慢的处置和较长的DA升高持续时间。从这些研究来看，BZT类似物的结构和物理化学性质似乎是决定其血脑屏障转运、处置和DA升高的因素。因此，我们的中心假设是，BZT类似物的BBB转运、PK和Pd取决于它们的结构修饰(例如，取代、对映体状态、亲脂性等)和由此产生的物理化学性质。为了检验这一假设，将追求以下具体目标：SA1。通过使用BBMECs检查结构和物理化学差异来确定BZT类似物的血脑屏障渗透性。SA2表征了大鼠静脉注射和口服BZT类似物后的脑摄取和PK。SA 3：用微透析法测定BZT类似物和可卡因在大鼠静脉注射和口服后的PD(例如，多巴胺释放)。Sa 4.研究精选BZT类似物与可卡因静脉注射和口服后的PK和PD相互作用。这些研究对于进一步评价替代疗法是至关重要的，并将阐明在有效药物治疗可卡因滥用所需的血脑屏障转运、PK和相关PD特征中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.