DISTRIBUTION, BIOTRANSFORMATION, STABILITY & EXCRETION OF OPIOID PEPTIDE DRUGS

该计划项目赠款旨在开发新的模式， 治疗和新的机制，以减轻疼痛和成瘾。 在本计划项目的前2年，P.I.已经发现 几种新的阿片类配体，强烈表明几种新的 获得非成瘾性阿片类镇痛剂的可能性， 治疗那些已经上瘾但希望 戒瘾。 在这部分拨款中，我们成功地 表明卤化取代可以显著改变 肽类药物在大脑中积累，也影响外周 镇痛效力 我们还描述了在体内的区域分布， 肽类药物在脑静脉注射后，并开发了一种新的 DPDPE的前药概念。 再加上我们成功地确定了 最佳途径将δ配体DPDPE递送到我们现在所处的CNS 立场，以解决几个新的假设如下：1。结构 亲脂性和氢键改变/修饰 选择性配体将改善局部脑（CNS） 积累 2.前体药物可用于增强肽药物递送， 特定组织贮库（即小肠与CNS）。 3.体外 牛脑内皮细胞测定可帮助预测体内血脑 势垒穿透 4.存在肽药物结构依赖性， 外周给药的具体途径。 我们的主要具体 目的是利用我们在化学和生物领域的丰富研究经验， 分析开发加上我们过去两年在描述 肽类药物的吸收、分布、代谢和排泄（ADME）， 将其应用于新的亲脂性和前药肽配体。 通过使用两者， 与体外牛脑内皮细胞偶联的体内脑分布 细胞模型，我们也将能够确定特定的肽药物 最佳BBB穿透的结构要求。 既然我们有 成功地表明，对稳定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，我们可以继续使用我们的 集成、分析、酶、代谢、分布和稳定性 技术来确定最佳的肽药物结构， 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.