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直接结合和抑制DA转运体有关。我们的专利化合物PD2007是一种高亲和力的DA转运抑制剂，具有理想的可卡因治疗药物的几个重要特征。PD2007对DA转运体的亲和力比可卡因高10倍。PD2007具有亲脂性，与良好的脑渗透一致，这在药代动力学研究中得到证实，表明PD2007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，PD2007在大脑中的半衰期比可卡因长14倍（PD2007大脑半衰期= 8.5小时）。PD2007 8.5小时的脑半衰期是可卡因治疗中一个理想的特征，这将允许实际的剂量方案。PD2007可卡因歧视研究和有条件的地方偏好研究表明，PD2007很少或没有滥用潜力。最重要的是，初步研究表明，预处理10 mg/kg的PD2007完全阻断了可卡因的兴奋作用。拟议的SBIR 1期研究将确定PD2007预处理是否阻断可卡因自我给药以及PD2007是否可以自我给药。确定PD2007预处理是否选择性地抑制大鼠可卡因剂量反应曲线。具体目标1B。确定PD2007是否在大鼠中自行给药。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：确定PD2007是否在猴子体内自行给药。在目前的申请中，我们提出临床前研究来评估我们的合适化合物PD2007是否在临床前研究中是有效的可卡因治疗药物。具体来说，我们将确定我们的多巴胺转运抑制剂PD2007是否能阻断大鼠和猴子的可卡因自我给药。可卡因治疗药物的另一个重要特性是，该化合物本身没有明显的滥用倾向。我们将通过确定PD2007是否在大鼠和猴子中自我给药来评估PD2007的滥用责任。预计PD2007将阻断这两个物种的可卡因自我给药，并且显示出很少或没有滥用潜力。这些结果表明PD2007作为可卡因治疗药物是进一步临床前开发的主要候选者。

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.