Pharmacology and Therapy for MDPV and alpha-PVP Like Drugs of Abuse

 描述（由申请人提供）：滥用被称为卡西酮或“浴盐”的非法药物是一个危险的和日益严重的世界性问题。该项目将重点关注两种医学上重要的卡西酮，MDPV和α-PVP。之所以选择这两种设计师精神兴奋剂药物，是因为它们最常与人类滥用和毒性有关。通过其作为去甲肾上腺素和多巴胺双重再摄取抑制剂的作用，它们引起CNS效应、心血管（CV）高血压和心动过速、激越、癫痫发作、暴力行为和死亡。科学证据表明，MDVP和α-PVP的（S）-异构体是产生中枢神经系统精神刺激作用的最有效立体异构体。因此，我们假设用抗（S）-MDPV和（S）-α-PVP的高亲和力单克隆抗体（mAb）治疗外消旋MDPV或α-PVP毒性可以保护滥用者免受有害的精神刺激作用。我们还将确定哪种异构体引起CV毒性，并产生针对最具活性的异构体形式的mAb药物。具体目的包括：1）开发用于评估抗卡西酮mAb在雄性和雌性大鼠中治疗效果的重要终点，2）合成用于制备高亲和力抗MDPV和α-PVP mAb的新型卡西酮样抗原半抗原，3）检测这些新疗法降低雄性和雌性大鼠中MDPV和α-PVP诱导的不良反应的能力。在成功完成这些研究后，我们将确定卡西酮立体异构体的相对医学重要性，并开发出第一种治疗卡西酮滥用的特定药物。

 DESCRIPTION (provided by applicant): Abuse of the class of illicit drugs known as cathinones or "bath salts" is a dangerous and growing worldwide problem. This project will focus on two medically important cathinones, MDPV and alpha-PVP. These two designer psychostimulant drugs were chosen because they are most often associated with human abuse and toxicity. Through their actions as dual reuptake inhibitors of norepinephrine and dopamine they elicit CNS effects, cardiovascular (CV) hypertension and tachycardia, agitation, seizures, violent behaviors, and death. Scientific evidence suggests the (S)-isomers of MDVP and alpha-PVP are the most potent stereoisomers for producing CNS psychoactive stimulant effects. Thus, we hypothesize that treatment of racemic MDPV or alpha-PVP toxicity with a high affinity monoclonal antibody (mAb) against (S)-MDPV and (S)-alpha-PVP can protect abusers from harmful psychoactive stimulant effects. We will also determine which isomer(s) cause CV toxicity, and generate mAb medications against the most active isomeric form. The specific aims include 1) development of important endpoints for assessing anti-cathinone mAb therapeutic efficacy in male and female rats, 2) synthesis of novel cathinone-like antigenic haptens for use in making a high affinity anti-MDPV and alpha-PVP mAb, 3) testing of the ability of these new therapies to reduce MDPV- and alpha-PVP-induced adverse effects in male and female rats. Upon successful completion of these studies we will have determined the relative medical importance of cathinone stereoisomers, and developed the first specific medication for treating cathinone abuse.