NEUROPEPTIDE FF ANTAGONISTS FOR TREATING OPIATE ABUSE

哺乳动物八肽FlQPQRFamide(F8Fa，神经肽Ff，NPFf)和 抗阿片肽，在阿片类药物依赖和随后的 禁欲综合症。因此，这种多肽的拮抗剂可以， 减轻对阿片类药物的耐受和依赖，并允许管理 阿片类戒断综合症。用作先导化合物的多肽拮抗剂 不到达中枢神经系统(CNS)后 给药，因为它不溶于脂类，不能穿透 血脑屏障。目标是开发这样的拮抗剂，可以 非肠道给药(静脉注射)注射、皮下注射等)， 并将药理活性物质输送到中枢神经系统(化学物质 交付系统，CDSS)。神经肽FF拮抗剂daYFLQPQRa(daY8Ra， 含有1-7个基团的N-末端脱氨基酪氨酸封闭肽酰胺 F8Fa的残基)作为先导化合物来设计CDS，该CDS呈现 将多肽脂溶，以增强被动进入中枢神经系统 转运，并允许在所附的CNS内进行酶转化 官能团，以防止多肽在 送货。最后，按顺序释放主动拮抗剂 新陈代谢。类似的daY8Ra也将通过a)删除 从d8ra，b)替换N-末端脱氨基酪氨酸的FlFQ片段 (天)含有N-烷基化烟酰胺残基的daY8Ra，以消除 需要一个活化步骤，以及c)通过结合a和b。化合物 将通过固相和溶液相合成的方法合成 连续延长多肽链，然后适当偶联 具有所需靶向性和保护性的多肽片段 功能基团。体外稳定性/新陈代谢研究将用于 确认设计的代谢变化的发生，并 研究代谢变化和研究代谢特性 对参与CNS靶向CNS的顺序生物激活至关重要 静脉注射后CDS的摄取和滞留向大鼠体内注射CDS 将通过测量拮抗剂的浓度和其浓度来评估 脑组织中的前体(S)随时间的变化。药理作用 对脑靶向NPFF拮抗剂的评估将包括准- 静脉注射诱发的吗啡戒断综合征。在大鼠体内的NPFF，以及 中枢神经靶向药理作用显著的NPFF拮抗剂 将通过使用戒断综合征来评估CDS方法 以纳洛酮参与吗啡依赖大鼠为研究范式。牙 喋喋不休/咀嚼，扭动/抓握，颤抖和颤抖，以及上睑下垂 将记录QMAS和纳洛酮参与的戒断措施 对于动物群体来说，化合物的效果将是 进行了统计评估。基于戒断症状的消退， 代谢稳定性数据和中枢神经系统分布研究，候选者将是 被选中用于进一步的基于结构的设计、生化、制药 和药理学研究，继续这些药物的临床前开发 潜在的新药。

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.