Novel 5-HT treatments for METH post-addiction therapy

用于冰毒成瘾后治疗的新型 5-HT 疗法

• 批准号: 7117432
• 负责人: CLARK E TEDFORD
• 金额: $ 35.81万
• 依托单位: OMEROS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117432
• 关键词: SDS polyacrylamide gel electrophoresis; behavior test; behavioral habituation /sensitization; cAMP response element binding protein; drug abuse chemotherapy; drug addiction antagonist; drug discovery /isolation; electrophysiology; fos protein; ketanserin; laboratory rat; methamphetamine; relapse /recurrence; serotonin; serotonin inhibitor; western blottings

DESCRIPTION (provided by applicant): The overall objective of this research is to identify putative drug treatments in the pre-clinical setting that can rapidly translate into post-withdrawal pharmacotherapy for methamphetamine (METH) addiction. Methamphetamine is an increasingly popular psychostimulant/hallucinogenic drug with an extremely high abuse liability. Presently, there is no cure for METH addiction. Indeed, the overwhelming majority (up to 85 percent) of patients undergoing modern-day drug rehabilitation relapse back into compulsive drug taking. Phase I studies have revealed that post-withdrawal administration of the 5-HT antagonist mianserin and mirtazapine, but not ketanserin reversed the sensitized behaviors established by METH, The establishment of the behavioral and biochemical paradigms at Solentix was successfully completed in 6 months and baseline as well as compound profiles have been generated for the agents mianserin, mirtazapine and ketanserin. The present SBIR grant phase II is posed to extend these basic questions to the clinical/commercial arena, with the objective of developing novel or identified 5-HT antagonists as potential treatments of METH addiction. A companion R01 grant has been awarded and initiated by Dr. Napier and will allow extensive basic research questions to be addressed on the involvement of 5-HT mechanisms and METH addiction, while the current SBIR grant will target commercialization activities of identified drug treatments. In addition, we have identified novel chemical structures that would be synthesized with the focused goal of developing the best pharmacological profile for reversal of METH-induced sensitization behavioral and biochemical events. The unique strengths of this grant are the focus on the drug-induced neuroadaptive changes in the brain, which will allow agents to be selected for METH drug addiction. The following aims are proposed: Five Specific Aims are proposed for the present SBIR Phase II. Specific Aims include: 1) Rodent behavioral METH-sensitization testing; 2) Novel chemistry synthesis; A patent has been filed to provide for the development of a large library of novel 5-HT compounds with specific substitutions that would provide unique receptor selectivity profiles. 3) In vitro drug screening and profiling; 4) Ex vivo CNS penetration testing; and 5) Drug Candidate - Biochemical & Electrophysiological Testing. The overall phase II SBIR goals will be to establish additional or novel drug candidates for METH addiction therapy through internal Omeros drug discovery efforts. The results of this research may also be utilized to explore additional therapeutic treatments for other drugs of abuse and subsequent identification of novel therapies.

描述（由申请人提供）：这项研究的总体目的是在临床前的环境中识别推定的药物治疗，这些药物可以迅速转化为甲基苯丙胺（METH）成瘾后的Drawdrdrawal药物治疗。甲基苯丙胺是一种越来越流行的精神刺激剂/致幻药，具有极高的滥用责任。目前，无法治愈甲基苯丙胺成瘾。的确，接受现代药物康复的患者中绝大多数（多达85％）重新恢复为强迫药物。第一阶段的研究表明，在5-HT拮抗剂甲梅蛋白和米氮平的静止后给药，但酮素蛋白不反转METH建立的敏感行为，在6个月内建立了Solentix的行为和生物化学范式在6个月内成功完成，并在6个月内完成了基线和基线prifine，并获得了整公司的成绩，并获得了MIRPILES MIRPILS，MIRPILS已成为MIRPILS MIRPILS MIRPILS MIRPILS。目前的SBIR赠款II阶段是为了将这些基本问题扩展到临床/商业领域，目的是开发新的或确定的5-HT拮抗剂作为甲基成瘾的潜在治疗方法。 Napier博士已授予和发起了同伴R01赠款，并将允许有关5-HT机制和MET成瘾的广泛基础研究问题，而当前的SBIR赠款将针对已识别药物治疗的商业化活动。此外，我们已经确定了新型的化学结构，这些化学结构将被合成，其重点目标是开发最佳的药理学特征，以逆转甲基苯丙胺诱导的敏化行为和生化事件。 这笔赠款的独特优势在于，重点是药物引起的大脑神经适应性变化，这将允许选择甲基药物成瘾的代理。提出了以下目的：针对本SBIR II期提出了五个具体目标。具体目的包括：1）啮齿动物行为甲基敏化测试； 2）新型化学合成；已提交专利，以提供具有新型5-HT化合物的大型库，并具有特定的替代品，可以提供独特的受体选择性曲线。 3）体外药物筛查和分析； 4）离体CNS渗透测试； 5）候选药物 - 生化和电生理测试。总体II期SBIR目标将是通过内部Omeros药物发现工作来建立其他或新颖的药物成瘾疗法。这项研究的结果也可以用于探索其他滥用药物的其他治疗疗法，并随后鉴定出新的疗法。