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（μ、δ、κ）阿片肽具有高亲和力和高选择性的肽和肽模拟物方面取得了巨大进展。 然而，这些合成阿片肽和肽模拟物的临床开发受到其不良生物制药性质（例如，通过肠粘膜和血脑屏障的渗透性低）的严重限制。在NIDA资助的支持下，我们设计并合成了一种模型阿片肽（DADLE）的酯酶敏感性环状前药，该前药具有有利于高跨细胞渗透的物理化学性质（疏水性，低氢键电位，不带电）。 然而，这些环状前药显示出对外排转运蛋白（例如MDR 1、MRP 2）的底物活性，这限制了它们穿过肠粘膜和血脑屏障的渗透。如果血脑屏障中的这些外排转运蛋白被抑制，则这些环状前药的“固有”渗透系数（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间集中于环状前药的生物制药性质的优化，包括：（i）使其外排转运蛋白的底物活性最小化，所述外排转运蛋白限制其肠粘膜和血脑屏障渗透，同时保持其良好的“内在”渗透特性;（ii）优化它们在靶组织（脑）中向DADLE的转化并使它们在血液隔室中的转化最小化;和（iii）最小化它们被肝脏清除以增加它们在血液中的停留时间，从而使前药分配穿过血脑屏障的机会最大化。本更新申请中提出的研究结果应允许设计阿片肽的第二代环状前药，其将在静脉内或口服给药后提供最佳药理学作用。

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.