NEUROPEPTIDE FF ANTAGONISTS FOR TREATING OPIATE ABUSE

用于治疗阿片类药物滥用的神经肽 FF 拮抗剂

• 批准号: 2462957
• 负责人: LASZLO PROKAI
• 金额: $ 6.9万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-09 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2462957
• 关键词: drug abuse chemotherapy; drug delivery systems; inhibitor /antagonist; laboratory rat; neuropeptides; nonhuman therapy evaluation; passive transport; pharmacology

The mammalian octapeptide FLQPQRFamide (F8Fa, neuropeptide FF, NPFF) an "anti-opioid" peptide, plays a role in opiate dependence and subsequent abstinence syndrome. An antagonist of this peptide may, therefore, alleviate opioid tolerance and dependence, and allow for the management of opiate abstinence syndrome. The peptide antagonist used as a lead compound does not reach the central nervous system (CNS) after systemic administration, because it is lipid-insoluble and unable to penetrate the blood-brain barrier. The objective is to develop such antagonists that can be administered parenterally (by i.v. injection, subcutaneously, etc.), and transport the pharmacologically active agents into the CNS (chemical delivery systems, CDSs). A neuropeptide FF antagonist daYFLQPQRa (daY8Ra, an N-terminal desaminotyrosine-blocked peptide amide containing the 1-7 residues of F8Fa) was used as a lead compound to design CDSs that renders the peptide lipid-soluble in order to enhance access to the CNS by passive transport, and allow enzymatic conversions within the CNS at the attached functional groups to prevent the peptide from leaving the CNS after delivery. Finally, the active antagonist is released by sequential metabolism. Analogs of daY8Ra will also be designed by a) removing the FLFQ segment from day8ra, b) by replacing the N-terminal desaminotyrosine (daY) of daY8Ra with an N-alkylated nicotinamide residue to eliminate the need for an activating step, and c) by combining a and b. The compounds will be synthesized by solid and solution-phase syntheses based on the sequential elongation of the peptide chain, then coupling appropriate peptide segments that possess the desired targeting and protecting functional groups. In vitro stability/metabolism studies will be used to confirm the occurrence of the designed metabolic changes and to investigate metabolic changes and to investigate metabolic properties crucial to the sequential bioactivation involved in CNS-targeting CNS- uptake and retention of the CDSs after i.v. injection of the CDSs to rats will be evaluated by measuring the concentration of the antagonist and its precursor(s) in brain tissue as a function of time. Pharmacological evaluation of the brain-targeted NPFF antagonists will include the quasi- morphine abstinence syndrome (QMAS) induced by i.c.v. NPFF in rats, and CNS-targeting of pharmacologically significant amount of NPFF antagonist by the CDS approach will be assessed by using the abstinence syndrome participated by naloxone in morphine-dependent rats as a paradigm. Teeth chattering/chewing, writhes/grasps, shakes and tremors, and ptosis as measures of the QMAS and naloxone-participated abstinence will be recorded for groups of animals, and the effect of the compounds will be statistically evaluated. Based on the attenuation of abstinence syndromes, metabolic stability data, and CNS-distribution studies, candidates will be selected for further structure-based design, biochemical, pharmaceutical and pharmacological studies that continue preclinical development of these potential new drugs.

哺乳动物八肽FLQPQRF酰胺（F8 Fa，神经肽FF，NPFF）和 “抗阿片”肽在阿片依赖和随后的 禁欲综合症因此，该肽的拮抗剂可以， 缓解阿片类药物耐受性和依赖性，并允许管理 鸦片戒断综合征用作先导化合物的肽拮抗剂 在全身性给药后不会到达中枢神经系统（CNS） 给药，因为它是脂不溶性的，不能渗透到 血脑屏障目的是开发这样的拮抗剂， 肠胃外给药（通过静脉注射、皮下注射等）， 并将促炎剂转运到CNS（化学物质 递送系统、CDS）。一种神经肽FF拮抗剂daYFLQPQRa（daY 8 Ra， N-末端脱氨基酪氨酸封闭的肽酰胺，其含有1-7 F8 Fa的残基）用作先导化合物来设计CDS， 肽脂溶性的，以增强通过被动 运输，并允许CNS内的酶促转化， 这些官能团防止肽在施用后离开CNS。 交付.最后，活性拮抗剂通过顺序释放， 新陈代谢. daY 8 Ra的类似物也将通过a）除去 来自第8天的FLFQ片段ra，B）通过替换N-末端脱氨基酪氨酸 (daY)的daY 8 Ra与N-烷基化烟酰胺残基反应以消除 需要活化步骤，和c）通过组合a和B。化合物 将通过固相和溶液相合成， 肽链的顺序延伸，然后适当偶联 具有所需靶向和保护作用的肽段 官能团。体外稳定性/代谢研究将用于 确认设计的代谢变化的发生，并 研究代谢变化并研究代谢特性 对CNS靶向CNS的顺序生物活化至关重要， 大鼠静脉注射CDS后CDS的吸收和保留 将通过测量拮抗剂的浓度及其 脑组织中的前体作为时间的函数。药理 脑靶向NPFF拮抗剂的评价将包括准- 大鼠i. c. v. NPFF诱导的吗啡戒断综合征（QMAS），以及 CNS靶向显著量的NPFF拮抗剂 将通过使用戒断综合征评估CDS方法 纳洛酮参与的吗啡依赖大鼠作为一个范例。牙齿 震颤/咀嚼、扭动/抓握、抖动和震颤以及上睑下垂， 将记录QMAS和纳洛酮参与的戒断措施 对于动物群体，化合物的效果将是 统计评估。基于戒断综合征的减轻， 代谢稳定性数据和CNS分布研究，候选人将 选择用于进一步的基于结构的设计、生物化学、制药 和药理学研究，继续临床前开发这些 潜在的新药