Novel 5-HT treatments for METH post-addiction therapy

描述(由申请人提供)：这项研究的总体目标是确定在临床前环境中可以迅速转化为甲基苯丙胺(冰毒)成瘾的停药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刺激/致幻药物，具有极高的滥用倾向。目前，冰毒成瘾还没有治愈方法。事实上，接受现代戒毒治疗的绝大多数(高达85%)的患者又回到了强迫吸毒的状态。第一阶段研究表明，停药后给予5-羟色胺拮抗剂米安色林和米氮平，但不能逆转由冰毒建立的致敏行为，Solentix的行为和生化范例的建立在6个月内成功完成，米安色林、米氮平和酮丝林的基线和化合物图谱已经生成。目前的SBIR第二阶段拨款是为了将这些基本问题扩展到临床/商业领域，目的是开发新的或已确定的5-羟色胺拮抗剂作为潜在的冰毒治疗方法。纳皮尔博士已经授予并发起了一项配套的R01赠款，将允许解决有关5-羟色胺机制和冰毒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，我们已经确定了将被合成的新的化学结构，重点是开发逆转冰毒诱导的致敏行为和生化事件的最佳药理学特征。 这项资助的独特优势是关注药物诱导的大脑神经适应性变化，这将允许为冰毒成瘾药物选择药物。目前的SBIR第二阶段提出了五个具体目标。具体目标包括：1)啮齿动物行为甲基敏化测试；2)新的化学合成；一项专利已经申请，以开发具有特定取代的新的5-羟色胺化合物的大型文库，将提供独特的受体选择性图谱。3)体外药物筛选和图谱；4)体外中枢神经系统渗透试验；5)候选药物--生化和电生理试验。第二阶段SBIR的总体目标将是通过Omeros内部的药物发现努力，为冰毒成瘾治疗建立更多或新的候选药物。这项研究的结果也可能被用来探索其他药物滥用的其他治疗方法，并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.