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: 6995103
• 负责人: CLARK E TEDFORD
• 金额: $ 42.56万
• 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/6995103
• 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）：本研究的总体目标是确定临床前环境中的假定药物治疗，这些治疗可以快速转化为甲基苯丙胺（METH）成瘾的戒断后药物治疗。甲基苯丙胺是一种日益流行的精神兴奋剂/致幻药物，具有极高的滥用可能性。目前，冰毒成瘾无法治愈。事实上，绝大多数（高达 85%）接受现代戒毒康复的患者都会再次陷入强迫性吸毒状态。 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 建立的敏化行为。Solentix 的行为和生化范式的建立在 6 个月内成功完成，基线为还生成了米安色林、米氮平和酮色林药剂的化合物谱。目前的 SBIR 第二阶段资助旨在将这些基本问题扩展到临床/商业领域，目的是开发新型或已确定的 5-HT 拮抗剂作为冰毒成瘾的潜在治疗方法。 Napier 博士已授予并发起了一项配套的 R01 拨款，该拨款将允许解决有关 5-HT 机制和冰毒成瘾的广泛基础研究问题，而当前的 SBIR 拨款将针对已确定药物治疗的商业化活动。此外，我们还确定了新的化学结构，其合成的重点目标是开发最佳药理学特征，以逆转冰毒诱导的致敏行为和生化事件。 这笔资助的独特优势是重点关注药物引起的大脑神经适应性变化，这将允许选择治疗冰毒成瘾的药物。提出了以下目标： 为当前的 SBIR 第二阶段提出了五个具体目标。具体目标包括： 1) 啮齿动物行为冰毒致敏测试； 2）新型化学合成；已申请一项专利，用于开发大型新型 5-HT 化合物库，这些化合物具有特定的取代基，可提供独特的受体选择性特征。 3）体外药物筛选和分析； 4）离体中枢神经系统渗透测试； 5) 候选药物 - 生化和电生理测试。 II 期 SBIR 的总体目标是通过 Omeros 内部药物发现工作，为冰毒成瘾治疗建立更多或新颖的候选药物。这项研究的结果也可用于探索其他滥用药物的额外治疗方法以及随后识别新疗法。