CYCLIC PRODRUGS OF OPIOID PEPTIDES

描述(申请人摘要)： 近年来，合成了大量具有高亲和力的多肽。 以及对不同类型的阿片类药物(Mu、Delta、Kappa)的选择性 多肽。这些阿片受体特异性多肽具有独特的药理作用。 保证其发展成为治疗剂的特性。然而， 在许多情况下，这些阿片肽的临床发展一直是 由于其较差的生物药学特性而被阻止[例如， 肠黏膜和血脑屏障的渗透性]。 在NIDA赠款的头两年里，我们证明了 阿片肽的环状前体药物一般具有明显更好的细胞 比阿片肽本身具有更强的渗透特性。这个 本次续签申请的主要目标包括：(I)展示 环状前体药物具有更好的口服生物利用度和更好的 血脑屏障在体内的渗透性优于阿片肽；(Ii)更好地定义 “化学连接物”的结构如何用来环化多肽和 阿片肽的结构本身会影响渗透 前药的特性，特别是它们的底物活性 外排系统(P-糖蛋白)，已被证明限制其 通过肠粘膜和血脑屏障的渗透；和(Iii)优化 前药对阿片肽的体内生物转化率 以便最大限度地发挥其药理作用。这些研究应该引领 以确定化学物质的最佳结构特征 连接物，当被用来制造阿片肽的环状前体药物时， 静脉注射后提供最佳的药理作用。或者是邮政总局。行政管理。

DESCRIPTION (Applicant's Abstract): In recent years, numerous peptides have been synthesized with high affinity and selectivity for the different types (mu, delta, kappa) of opioid peptides. These opioid receptor-specific peptides have unique pharmacology properties that warrant their development as therapeutic agents. However, in many cases, the clinical development of these opioid peptides has been prevented because of their poor biopharmaceutical properties [e.g., permeation across the intestinal mucosa and blood-brain barrier (BBB)]. During the first two years of this NIDA grant, we have demonstrated that cyclic prodrugs of opioid peptides in general have significantly better cell permeation characteristics than do the opioid peptides themselves. The major objectives of this renewal application include: (i) to demonstrate that the cyclic prodrugs have better oral bioavailability and better permeation of the BBB in vivo than the opioid peptides; (ii) better define how the structure of the "chemical linker" used to cyclize the peptide and the structure of the opioid peptide, itself, influence the permeation characteristics of the prodrugs, particularly their substrate activity for efflux systems (P-glycoproteins), which have been shown to limit their permeation through the intestinal mucosa and the BBB; and (iii) to optimize the bioconversion rates of the prodrugs to the opioid peptides in vivo in order to maximize their pharmacological effects. These studies should lead to the identification of the optimal structural features of the chemical linkers that when employed to make cyclic prodrugs of opioid peptides will afford optimal pharmacological effects after i.v. or p.o. administration.