COCAINE THERAPEUTIC: PD2007

描述（由申请人提供）：广泛的研究表明，可卡因的滥用潜力与DA转运蛋白的直接结合和抑制有关。我们的专利化合物PD 2007是一种高亲和力DA转运抑制剂，具有理想可卡因治疗的几个重要特征。PD 2007对DA转运蛋白的亲和力比可卡因高10倍。PD 2007是亲脂性的，与良好的脑渗透一致，这已经在药代动力学研究中得到证实，表明PD 2007在脑中的浓度比可卡因高几倍。这些相同的药代动力学研究表明，PD 2007在脑中的半衰期比可卡因长14倍（PD 2007脑半衰期= 8.5小时）。PD 2007的8.5小时脑半衰期是可卡因治疗剂的理想特征，其将允许实际的给药方案。PD 2007可卡因歧视研究和条件性位置偏好研究表明，PD 2007几乎没有滥用潜力。最重要的是，初步研究表明，用10 mg/kg PD 2007预处理完全阻断了可卡因的刺激作用。拟定的SBIR I期研究将确定PD 2007预处理是否阻断可卡因自我给药以及PD 2007是否为自我给药，我们的具体目的是：具体目的1A。确定PD 2007预处理是否选择性抑制大鼠中可卡因的剂量-反应曲线。具体目标1B。确定PD 2007是否在大鼠中自我给药。具体目标1C。确定PD 2007预处理是否选择性抑制猴中可卡因的剂量-反应曲线。具体目标1D。确定PD 2007是否在猴中自我给药。在本申请中，我们提出临床前研究以评估我们的适当化合物PD 2007在临床前研究中是否是有效的可卡因治疗剂。具体来说，我们将确定我们的多巴胺转运抑制剂PD 2007是否能阻断大鼠和猴子的可卡因自我给药。可卡因治疗剂的另一个重要特性是该化合物本身不显示出显著的滥用倾向。我们将通过确定PD 2007是否在大鼠和猴中自我给药来评估PD 2007的滥用倾向。预计PD 2007将阻断两种物种中的可卡因自我给药，并显示出很少或没有滥用潜力。这些结果表明，PD 2007是进一步临床前开发作为可卡因治疗剂的主要候选药物。

DESCRIPTION (provided by applicant): Extensive research suggests that cocaine's abuse potential is associated with direct binding and inhibition of the DA transporter. Our proprietary compound, PD2007 is a high affinity DA transport inhibitor that possesses several important characteristics of an ideal cocaine therapeutic. PD2007 has a 10-fold higher affinity for the DA transporter than cocaine. PD2007 is lipophilic consistent with good penetration into brain which has been confirmed in pharmacokinetic studies indicating that PD2007 is concentrated in brain at several fold higher concentrations than cocaine. These same pharmacokinetic studies indicated that PD2007's half-life in brain was 14-fold longer than cocaine (PD2007 brain half-life = 8.5 hr). PD2007's 8.5 hr brain half-life is an ideal characteristic in a cocaine therapeutic that would allow practical dosing regimes. PD2007 cocaine-discrimination studies and conditioned place preference studies indicate that PD2007 has little or no abuse potential. And most importantly, Preliminary Studies indicate the pretreatment with 10 mg/kg PD2007 completely blocked the stimulant effects of cocaine. The proposed SBIR Phase 1 studies will determine if pretreatment with PD2007 blocks cocaine self-administration and whether PD2007 is self-administered, our Specific Aims are: Specific Aim 1A. Determine if PD2007 pretreatment selectively depresses the cocaine dose- response curve in rats. Specific Aim 1B. Determine if PD2007 is self-administered in rats. Specific Aim 1C. Determine if PD2007 pretreatment selectively depresses the cocaine dose- response curve in monkeys. Specific Aim 1D. Determine if PD2007 is self-administered in monkeys. In the present application, we propose preclinical studies to assess whether our propriety compound, PD2007, is an effective cocaine therapeutic in preclinical studies. Specifically, we will determine if our dopamine transport inhibitor, PD2007, blocks cocaine self-administration in both rats and monkeys. An additional important property of a cocaine therapeutic is that the compound does not demonstrate significant abuse liability itself. We will assess the abuse liability of PD2007 by determining whether PD2007 is self-administered in both rats and monkeys. It is anticipated that PD2007 will block cocaine self-administration in both species and demonstrate little or nor abuse potential. Such results would indicate that PD2007 is a prime candidate for further preclinical development as a cocaine therapeutic.