Novel 5-HT treatments for METH post-addiction therapy

描述（由申请人提供）：本研究的总体目标是在临床前环境中确定可以快速转化为甲基苯丙胺（METH）成瘾戒断后药物治疗的假定药物治疗。甲基苯丙胺是一种越来越受欢迎的精神兴奋剂/致幻药物，具有极高的滥用倾向。目前，没有治愈METH成瘾的方法。事实上，绝大多数（高达85%）接受现代戒毒治疗的患者会重新陷入强迫性吸毒。I期研究表明，停药后给予5-HT拮抗剂米安色林和米氮平（但不是酮色林）可逆转METH建立的致敏行为。在6个月内成功完成了Solentix的行为和生化模式建立，并生成了米安色林、米氮平和酮色林的基线和化合物特征。目前的SBIR资助第二阶段是为了将这些基本问题扩展到临床/商业竞技场，目的是开发新的或确定的5-HT拮抗剂作为METH成瘾的潜在治疗。纳皮耶博士已授予并发起了一项配套的R 01赠款，该赠款将允许解决有关5-HT机制和METH成瘾的广泛基础研究问题，而目前的SBIR赠款将针对已确定的药物治疗的商业化活动。此外，我们已经确定了新的化学结构，将与开发最佳的药理学概况逆转的甲基诱导的致敏行为和生化事件的重点目标合成。 该补助金的独特优势是专注于大脑中药物诱导的神经适应性变化，这将允许选择用于METH药物成瘾的药物。提出了以下目标：为目前SBIR第二阶段提出了五个具体目标。具体目标包括：1）啮齿动物行为MET致敏试验; 2）新型化学合成;已经申请了一项专利，以提供具有特定取代的新型5-HT化合物的大型库的开发，所述特定取代将提供独特的受体选择性概况。3)体外药物筛选和分析; 4）离体CNS渗透测试;和5）候选药物-生化和电生理测试。SBIR第二阶段的总体目标是通过Omeros内部的药物发现工作，为METH成瘾治疗建立额外的或新型的候选药物。这项研究的结果也可用于探索其他滥用药物的其他治疗方法，以及随后确定新的治疗方法。

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.