Norketamine for Treatment of Pain

慢性疼痛是一个重大的医学问题。它的治疗，特别是慢性神经病理性疼痛，仍然存在 治疗需求未得到满足的领域。治疗神经性疾病的一类重要的潜在药物 疼痛是作为N-甲基-D-天冬氨酸(NMDA)受体拮抗剂的化合物。毒品来源 这类药物还被证明可以增强吗啡的止痛效果并抑制耐受性。 这种阿片类药物的发展。尽管它们作为镇痛剂有很大的前景，但唯一的临床用途是 现有的NMDA受体拮抗剂氯胺酮由于其拟精神分裂症、镇静和 运动副作用。这促使人们努力寻找其他NMDA受体拮抗剂， 保留止痛特性，但具有更可接受的副作用。为这项工作提供第一阶段科技成果转移权资金 Project已经证明了新型NMDA受体拮抗剂去甲氯胺酮(NK)及其对映体 [r(+)和S(-)-NK]在神经病理性疼痛的啮齿动物模型中具有镇痛作用。两边的大多数 作用与R(+)-对映体有关。因此，我们已经确定了去甲氯胺酮，特别是 S(-)-NK作为一种治疗神经病理性疼痛的新药具有开发潜力。这个 拟议的第二阶段STTR资金的最终目标是开发一种NMDA受体拮抗剂， 治疗慢性疼痛的副作用更少、更容易耐受。第二阶段的具体目标 STTR的建议是：1)进一步表征S(-j-NK，与R(+)-对照)的药理特征。 NK，在已建立的大鼠疼痛和行为模型中；2)进行非cGMP批量合成S(-)-NK用于 临床前研究；3)评价口服生物利用度，评估代谢谱，并确定 S(-)-NK大鼠的最佳口服剂量；4)为原料药提供原料药的原料药制备工艺，制备口服液 S(-)-NK胶囊剂型及获得cGMP S(-)-NK和cGMP安慰剂用于I期临床 试验；5)评价S(-)-NK的毒理性质，包括神经毒性；6)进行I期临床试验 目的：评价S(-)NK的安全性。总括而言，第一阶段的研究结果已确定S(- )-NK是进一步开发为治疗神经病理性疼痛的药物的可行候选者。第二期沙田公路 提案将以第一阶段STTR研究结果为基础，进一步确定其药理学和毒理学特征 S(-)-NK，获得研究性新药申请，总目标是进入第一阶段 在人体上进行临床试验。一种临床上有用的治疗慢性神经性疼痛的药物的开发将有 潜在的广泛应用于治疗疼痛，包括癌症、艾滋病、神经病变、糖尿病神经病变、 复杂的区域疼痛综合征和神经根病。

Chronic pain is a significant medical problem. Its treatment, in particular chronic neuropathic pain, remains an area of unmet therapeutic need. An important potential group of drugs for the treatment of neuropathic pain are compounds which act as antagonists at the N-methyl-D-aspartate (NMDA) receptor. Drugs from this class have also been shown to enhance the analgesic effect of morphine and to inhibit tolerance development to this opioid. Despite their great promise as analgesics, the clinical usefulness of the only available NMDA receptor antagonist, ketamine, has been limited due to its psychotomimetic, sedative and motor side effects. This has prompted an effort towards identifying other NMDA receptor antagonists which retain analgesic properties but with a more acceptable side effect profile. Phase I STTR funding for this project has demonstrated that the novel NMDA receptor antagonist, norketamine (NK) and its enantomers [R(+) and S(-)-NK] have analgesic properties in a rodent model of neuropathic pain. The majority of side effects are with the R(+)-enantiomer. Thus, we have established the feasibility that norketamine, specifically S(-)-NK, has the potential for development as a novel agent for the treatment of neuropathic pain. The ultimate objective in the proposed Phase II STTR funding is to develop an NMDA receptor antagonist with fewer and more tolerable side effects for the treatment of chronic pain. The specific aims of the Phase II STTR proposal are to: 1) further characterize the pharmacologic profile of S(-j-NK, in comparison to R(+)- NK, in established rat models of pain and behavior; 2) perform non-cGMP bulk synthesis of S(-)-NK for preclinical studies; 3) evaluate the oral bioavailability, assess the metabolic profile, and determine the optimal oral dose of S(-)-NK in the rat; 4) provide a bulk manufacturing process for the API, formulate an oral capsule dosage form of S(-)-NK and obtain cGMP S(-)-NK and cGMP placebo for use in the Phase I clinical trial; 5) evaluate toxicological properties of S(-)-NK including neurotoxicity; 6) conduct a Phase I clinical trial to assess the safety of S(-) NK. In summary, Phase I STTR findings have established the feasibility that S(- )-NK is a viable candidate for further development as a drug for neuropathic pain. The Phase II STTR proposal will build upon Phase I STTR findings to further characterize the pharmacology and toxicology of S(-)-NK, to obtain an Investigational New Drug application, with the overall goal of proceeding to a Phase I clinical trial in humans. The development of a clinically useful drug for chronic neuropathic pain will have potential broad application for the treatment of pain including cancer, AID'S, neuropathy, diabetic neuropathy, complex regional pain syndrome and radiculopathy.