DISTRIBUTION, BIOTRANSFORMATION, STABILITY & EXCRETION OF OPIOID PEPTIDE DRUGS

该计划项目赠款旨在开发新的模式 缓解疼痛和成瘾的治疗和新机制。 在这个项目的头两年里，私家侦探S发现 几类新的阿片类配体强烈地暗示了几种新的 获得非成瘾性阿片类镇痛剂的可能性，并可能 治疗那些已经上瘾的人的新方法 戒掉毒瘾。在这一部分的赠款中，我们成功地 研究表明，卤化替代可以显著改变 多肽药物积聚在大脑中，也影响外周 止痛剂的效力。我们还描述了活体内的区域分布 静脉注射后大脑中的多肽药物。管理并开发了一种新的 DPDPE的亲药物概念。再加上我们成功地确定了 将Delta型配体DPDPE运送到我们现在所在的CNS的最佳路线 解决以下几个新假设的立场如下：1.结构性 三角洲的亲脂性和氢键变化/修饰 选择性配体将改善区域脑(CNS) 积累。2.前体药物可用于增强多肽药物的递送 特定的组织储存库(即小肠与中枢神经系统)。3.体外实验 牛脑内皮细胞检测有助于预测活体血脑 障碍穿透。4.存在多肽药物结构依赖性。 外周用药的具体途径。我们的主要特效药 目标是利用我们在化学和生物方面的广泛研究经验 化验发展与我们过去两年的成功描述相结合 多肽药物吸收、分布、代谢和排泄(ADME)和 将其应用于新的亲脂性和亲药物的多肽配体。通过在中同时使用两者 牛脑内皮细胞体外偶联的活体脑分布 细胞模型我们也将能够确定特定的多肽药物 最佳BBB穿透的结构要求。因为我们有 成功地证明了对稳定多肽类似物的某些修饰 改变中枢神经系统的积累我们有信心可以继续使用我们的 综合、分析、酶、代谢、分布和稳定性 确定最佳多肽药物结构的技术 临床应用。

This program project grant is designed to develop new modalities of treatment and new mechanisms for the relief from pain and addiction. During the first 2 years of this Program Project the P.I.'s have discovered several new classes of opioid ligands that strongly suggest several new possibilities for obtaining non-addictive opioid analgesics, and possibly new modalities for the treatment of those already addicted who wish to withdraw from addiction. In this section of the grant we have successfully shown that halogenation substitution can dramatically alter the level of peptide drug accumulated in the brain and also affects the peripheral analgesic potency. We have also described in vivo regional distribution of peptide drugs in the brain after i.v. administration and developed a new pro-drug concept for DPDPE. Coupled to our success with determining the optimal route delivering the delta ligand DPDPE to the CNS we are now in the position to address several new hypotheses as follows: 1. Structural lipophilic and hydrogen bonding alterations/modifications in delta selective ligands will lead to improvements in regional brain (CNS) accumulation. 2. Pro-drugs can be used to enhance peptide drug delivery to specific tissue depots (i.e. small intestine versus CNS). 3. In Vitro bovine brain endothelial cell assays can help predict in vivo blood brain barrier penetration. 4. There is a peptide drug structure dependency to the specific route of peripheral drug administration. Our main Specific Aim is to use our extensive research experience in chemical and biological assay development coupled to our past two years of success in describing peptide drug absorption, distribution, metabolism and excretion (ADME) and apply it to new lipophilic and pro-drug peptide ligands. By using both in vivo brain distribution coupled to the in vitro bovine brain endothelial cell model we will also be able to determine the specific peptide drug structural requirements for optimal BBB penetration. Since we have successfully shown that certain modifications to stable peptide analogues alter CNS accumulation we are confident that we can continue to use our integrated, analytical, enzymatic, metabolic, distribution and stability techniques to determine the most optimal peptide drug structure for clinical application.