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转运体的直接结合和抑制有关。我们的专利化合物PD2007是一种高亲和力的DA转运抑制剂，具有理想可卡因疗法的几个重要特征。PD2007对DA转运蛋白的亲和力是可卡因的10倍。PD2007是亲脂性的，与良好的脑渗透一致，这已在药代动力学研究中得到证实，表明PD2007在大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，PD2007的S在脑内的半衰期是可卡因的14倍(PD2007的脑半衰期=8.5小时)。PD2007的S 8.5小时的大脑半衰期是可卡因疗法的一个理想特征，它将允许实际的剂量制度。PD2007可卡因歧视研究和条件性场所偏好研究表明，PD2007的滥用潜力很小或根本没有。最重要的是，初步研究表明，预先给予10 mg/kg的PD2007完全阻断了可卡因的刺激作用。拟议的SBIR第一阶段研究将确定PD2007是否阻止可卡因的自我给药，以及PD2007是否自我给药，我们的具体目标是：具体目标1A。确定PD2007预处理是否选择性地抑制大鼠的可卡因剂量-反应曲线。具体目标1B。确定PD2007是否在大鼠体内自我给药。具体目标1C。确定PD2007预处理是否选择性地抑制猴子的可卡因剂量-反应曲线。具体目标1D。确定PD2007是否在猴子体内自我给药。在目前的应用中，我们建议进行临床前研究，以评估我们的适当化合物PD2007在临床前研究中是否是一种有效的可卡因疗法。具体地说，我们将确定我们的多巴胺转运抑制剂PD2007是否能阻止大鼠和猴子体内的可卡因自我给药。可卡因治疗药物的另一个重要性质是，该化合物本身并不表现出明显的滥用责任。我们将通过确定PD2007在大鼠和猴子身上是否自我给药来评估PD2007的滥用责任。预计PD2007将阻止这两个物种的可卡因自我给药，并显示出很少或根本不会滥用的潜力。这样的结果将表明PD2007是进一步作为可卡因治疗药物的临床前开发的最佳候选药物。

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.