CYCLIC PRODRUGS OF OPIOID PEPTIDES

描述（申请人摘要）： 近年来，人们合成了许多具有高亲和力的多肽 和对不同类型（μ、δ、κ）阿片样物质的选择性 缩氨酸 这些阿片受体特异性肽具有独特的药理作用 这些特性保证了它们作为治疗剂的开发。 然而，在这方面， 在许多情况下，这些阿片肽的临床开发已经被 由于它们差的生物制药性质而被阻止[例如， 透过肠粘膜和血脑屏障（BBB）]。 在NIDA赠款的头两年，我们已经证明， 阿片肽的环状前药通常具有显著更好的细胞毒性， 渗透特性比阿片肽本身。 的 本续期申请的主要目的包括：（i）证明 环状前药具有更好的口服生物利用度和更好的 （ii）与阿片肽相比，更好地定义了BBB在体内的渗透; 用于环化肽的“化学接头”的结构和 阿片肽本身的结构影响渗透 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BBB的渗透;和（iii）优化 前药在体内向阿片肽的生物转化率 以最大限度地发挥其药理作用。 这些研究将导致 识别化学物质的最佳结构特征 当用于制备阿片肽的环状前药时， 在i. v.或p.o.局

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.