Development of I-THP as New Medication for Drug Addiction (DP1)

描述（由申请人提供）：有效治疗可卡因成瘾的首要挑战是缺乏FDA批准的药物治疗这种非法药物。该DP1提案直接解决了这一问题，通过进行临床I/II期药物开发和评估研究，以确定l-四氢巴马汀（l-THP）作为可卡因依赖的抗成瘾药物的有效性和安全性。l-THP是从中药延胡索中分离出来的一种主要的活性单体化合物，在中国作为镇痛药（商品名：罗通定）在临床上已经使用了40多年。据报道，l-THP作为DP1部分激动剂/D2拮抗剂作用于多巴胺（DA）受体，并与D3受体相互作用。此外，它对α 1和5HT1A受体具有低亲和力结合。l-THP减弱大鼠可卡因自我给药和脑刺激奖励，缓解海洛因成瘾者的渴望。l-THP作用的机制尚不清楚。这可能与多巴胺受体的活性有关，因为多巴胺能系统在激活大脑奖励通路中起着关键作用。更重要的是，l-THP可能与多个单胺受体结合，提供“天然鸡尾酒样可卡因拮抗剂”的功效。因为，众所周知，可卡因非选择性地抑制几种单胺转运蛋白。然而，独特的药理学特征使l-THP成为抗成瘾药物的优秀候选人。中国几十年来对l-THP的大量动物和临床前药理学和毒性研究数据为我们提出的转化研究提供了坚实的安全性基础。我们计划从FDA获得l-THP的IND批准，之后我们将进行临床I期和II期试验。如果从动物研究到人类临床研究的过渡是成功的，它将为l-THP是一种有效的可卡因成瘾药物的概念提供证据。

DESCRIPTION (provided by applicant): The foremost challenge to the effective treatment of cocaine addiction is the lack of FDA approved pharmacotherapy for this illicit drug. This DP1 proposal directly addresses this concern by performing clinical Phase I/II medication development and evaluation studies to determine the efficacy and safety of l-tetrahydropalmatine (l-THP) as an anti-addiction medication for cocaine dependence. l-THP, a major active single compound isolated from the Chinese herbal medicine Yanhusuo, has been used in clinical practice as an analgesic (commercial name: Rotundine) in China for more than 40 years. It has been reported that l-THP acts on dopamine (DA) receptors as a DP1 partial agonist/D2 antagonist and also interacts with D3 receptor. In addition, it has low affinity binding to alpha1 and 5HT1A receptors. l-THP attenuates cocaine self-administration and brain-stimulation reward in rats and relieves craving in heroin addicts. The mechanism for this action of l-THP is unknown. It could be related to its DA receptor activity, as the dopaminergic system plays a critical role in the activation of brain reward pathways. More importantly, it could be that l-THP binds to multiple monoamine receptors that provide efficacy as "a natural cocktail-like cocaine antagonist." Since, it is well known that cocaine non-selectively inhibits several monoamine transporters. Nevertheless, the unique pharmacological profile makes l-THP an excellent candidate for anti-addiction medication. The extensive animal and preclinical pharmacology and toxicity data resulting from decades of studies on l-THP in China provide a solid safety foundation for our proposed translational study. We plan to obtain IND approval of l-THP from the FDA, after which we will conduct clinical phase I and phase II trials. If this transition from animal studies to human clinical studies is successful, it will provide proof of concept that l-THP is an effective medication for cocaine addiction.