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确定临床前假定的药物治疗方法，这些药物治疗方法可以迅速转化为戒断后的药物治疗，以治疗甲基苯丙胺（冰毒）成瘾。甲基苯丙胺是一种日益流行的精神兴奋剂/致幻药物，具有极高的滥用风险。目前，还没有治愈冰毒成瘾的方法。事实上，绝大多数（高达85%）正在接受现代药物康复治疗的病人又重新开始强迫性服药。I期研究表明，戒断后给予5-羟色胺拮抗剂米安色林和米氮平，而不是酮色林，逆转了甲基安非他命建立的致敏行为。索伦提克斯的行为和生化范式的建立在6个月内成功完成，基线以及米安色林，米氮平和酮色林的化合物谱已经生成。目前的SBIR资助II期旨在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-羟色胺拮抗剂作为冰毒成瘾的潜在治疗方法。由Napier博士颁发并发起的R01资助将允许广泛的基础研究问题得到解决，涉及5-HT机制和冰毒成瘾，而目前的SBIR资助将针对已确定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，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致敏行为和生化事件。

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.