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

 描述(申请人提供)：滥用一类被称为卡西酮或“浴盐”的非法药物是一个危险且日益严重的世界性问题。该项目将专注于两种医学上重要的卡西酮，MDPV和α-PVP。之所以选择这两种特制的精神刺激药物，是因为它们最常与人的虐待和毒性有关。通过它们作为去甲肾上腺素和多巴胺的双重再摄取抑制剂的作用，它们引起中枢神经系统效应、心血管(CV)高血压和心动过速、激动、癫痫、暴力行为和死亡。科学证据表明，MDVP和α-PVP的(S)-异构体是产生中枢精神兴奋作用的最有效的立体异构体。因此，我们推测，用高亲和力的抗(S)-MDPV和(S)-α-PVP的单抗治疗外消旋MDPV或α-PVP中毒可以保护吸毒者免受有害的精神活性兴奋剂的影响。我们还将确定哪个异构体(S)会导致CV毒性，并产生针对最活跃的异构体的单抗药物。具体目标包括：1)开发用于评估抗卡西酮单抗在雄性和雌性大鼠中的疗效的重要终点；2)合成新的卡西酮类抗原半抗原，用于制备高亲和力的抗MDPV和α-PVP单抗；3)测试这些新疗法减少MDPV和α-PVP对雄性和雌性大鼠的不良反应的能力。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尼酮滥用的特定药物。

 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.