Cyclic Prodrugs of Opioid Peptides

描述（由申请人提供）：近年来，在设计和合成对不同类型（mu, delta, kappa）的阿片肽具有高亲和力和高选择性的肽和拟肽物方面取得了巨大进展。然而，这些合成阿片肽和拟肽制剂的临床开发受到其生物制药性能差（如通过肠黏膜和血脑屏障的渗透性低）的严重限制。在NIDA的资助下，我们设计并合成了一种模型阿片肽（DADLE）的酯酶敏感环前药，该模型阿片肽具有有利于高跨细胞渗透的理化性质（疏水性，低氢键电位，无电荷）。然而，这些环状前药显示出对外排转运蛋白（如MDR1， MRP2）的底物活性，这限制了它们通过肠粘膜和血脑屏障的渗透。如果这些外排转运蛋白在血脑屏障中被抑制，这些环前药的“固有”渗透性系数（Papp）比DADLE本身的Papp值高100-300倍。基于这些令人兴奋的观察结果，我们计划在下一个资助期内重点优化环前药的生物制药特性，包括：(i)最小化其外排转运体的底物活性，这些底物活性限制了其肠粘膜和血脑屏障的渗透，同时保持其良好的“内在”渗透特性；（ii）优化其在靶组织（脑）中向DADLE的转化，并最大限度地减少其在血室中的转化；（iii）尽量减少肝脏对它们的清除，从而增加它们在血液中的停留时间，从而最大限度地增加前药穿过血脑屏障的机会。本更新申请中提出的研究结果应允许设计第二代阿片肽环前药，这些药物将在静脉或口服给药后提供最佳药理作用。

DESCRIPTION (provided by applicant): Tremendous progress has been made in recent years in the design and synthesis of peptides and peptidomimetics with high affinity and high selectivity for the different types (mu, delta, kappa) of opioid peptides. However, the clinical development of these synthetic opioid peptides and peptidomimetics has been seriously limited by their poor biopharmaceutical properties (e.g. low permeation through the intestinal mucosa and the blood-brain barrier). With support from this NIDA grant, we have designed and synthesized esterase-sensitive cyclic prodrugs of a model opioid peptide (DADLE) that exhibit physicochemical properties (hydrophobicity, low hydrogen bonding potential, no charge) favorable for high transcellular permeation. However, these cyclic prodrugs were shown to exhibit substrate activity for efflux transporters (e.g. MDR1, MRP2) which restrict their permeation across the intestinal mucosa and the blood-brain barrier. If these efflux transporters in the blood-brain barrier are inhibited, the "intrinsic" permeability coefficients (Papp) of these cyclic prodrugs are 100-300 fold higher than the Papp value for DADLE itself. Based on these exciting observations, we plan during the next grant period to focus on the optimization of the bio-pharmaceutical properties of the cyclic prodrugs, including: (i) minimizing their substrate activity for the efflux transporters that limit their intestinal mucosal and blood-brain barrier permeation while maintaining their good "intrinsic" permeation characteristics; (ii) optimizing their conversion to DADLE in the target tissue (brain) and minimizing their conversien in the blood compartment; and (iii) minimizing their clearance by the liver so as to increase their residency time in the blood, thus maximizing the opportunity for the prodrug to partition across the blood-brain barrier. The results of the studies proposed in this renewal application should allow for the design of second generation cyclic prodrugs of opioid peptides that will afford optimal pharmacological effects after i.v. or oral administration.